<?xml version="1.0" encoding="UTF-8"?><rss version="2.0"
	xmlns:content="http://purl.org/rss/1.0/modules/content/"
	xmlns:wfw="http://wellformedweb.org/CommentAPI/"
	xmlns:dc="http://purl.org/dc/elements/1.1/"
	xmlns:atom="http://www.w3.org/2005/Atom"
	xmlns:sy="http://purl.org/rss/1.0/modules/syndication/"
	xmlns:slash="http://purl.org/rss/1.0/modules/slash/"
	>

<channel>
	<title>Creative Biolabs Exosome Blog</title>
	<atom:link href="https://www.creative-biolabs.com/blog/exosome/feed/" rel="self" type="application/rss+xml" />
	<link>https://www.creative-biolabs.com/blog/exosome</link>
	<description></description>
	<lastBuildDate>Tue, 05 Nov 2024 15:09:00 +0000</lastBuildDate>
	<language>en-US</language>
	<sy:updatePeriod>
	hourly	</sy:updatePeriod>
	<sy:updateFrequency>
	1	</sy:updateFrequency>
	<generator>https://wordpress.org/?v=6.3.1</generator>

<image>
	<url>https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2020/11/cropped-favicon-32x32.png</url>
	<title>Creative Biolabs Exosome Blog</title>
	<link>https://www.creative-biolabs.com/blog/exosome</link>
	<width>32</width>
	<height>32</height>
</image> 
	<item>
		<title>Engineering Extracellular Vesicles for Diagnostics and Therapeutics</title>
		<link>https://www.creative-biolabs.com/blog/exosome/exosome-review/engineering-extracellular-vesicles-for-diagnostics-and-therapeutics/</link>
		
		<dc:creator><![CDATA[biolabs]]></dc:creator>
		<pubDate>Mon, 28 Oct 2024 09:56:58 +0000</pubDate>
				<category><![CDATA[Exosome Review]]></category>
		<guid isPermaLink="false">https://www.creative-biolabs.com/blog/exosome/?p=395</guid>

					<description><![CDATA[Therapeutic approaches based on extracellular vesicles (EVs) are attracting significant attention in drug delivery, immunotherapy, and regenerative medicine. However, the clinical translation of EVs is hindered by challenges such as limited yield,<a class="moretag" href="https://www.creative-biolabs.com/blog/exosome/exosome-review/engineering-extracellular-vesicles-for-diagnostics-and-therapeutics/">Read More...</a>]]></description>
										<content:encoded><![CDATA[<p><span style="font-size: 15px;">Therapeutic approaches based on extracellular vesicles (EVs) are attracting significant attention in drug delivery, immunotherapy, and regenerative medicine. However, the clinical translation of EVs is hindered by challenges such as limited yield, functional heterogeneity, and inadequate targeting specificity. Enhancing the inherent functions of EVs and endowing them with additional functionalities holds promise for accelerating their clinical application. Bioorthogonal click chemistry has garnered widespread interest due to its ability to modify EVs in a controlled and specific manner without disrupting their intrinsic structure. This approach was further highlighted by the Nobel Prize in Chemistry in 2022, underscoring its advantages. Numerous studies have already demonstrated the substantial potential of bioorthogonal labeling in EV separation, imaging, and therapy.</span></p>
<p><span style="font-size: 15px;">Recently, scientists published a review titled &#8220;Engineering extracellular vesicles for diagnosis and therapy&#8221; in Trends in Pharmacological Sciences. The paper primarily introduces the latest advancements in engineering EVs using bioorthogonal click chemistry. It outlines labeling strategies for engineered EVs and discusses their advantages, focusing on applications in EV separation and purification, diagnostics, and therapeutic interventions. Notably, the review emphasizes the use of bioorthogonal glycan metabolic engineering in vesicles for targeted <em>in vivo</em> therapy. The article also provides insights into the future prospects of EV engineering technologies.</span></p>
<p><span style="font-size: 15px;"><img decoding="async" fetchpriority="high" class="aligncenter  wp-image-396" src="http://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/11/1.png" alt="" width="619" height="120" srcset="https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/11/1.png 948w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/11/1-300x58.png 300w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/11/1-768x148.png 768w" sizes="(max-width: 619px) 100vw, 619px" /></span><span style="font-size: 15px;">Therapeutic approaches based on extracellular vesicles (EVs) have garnered substantial attention in the fields of drug delivery, immunotherapy, and regenerative medicine. To address the challenges limiting the clinical translation of EVs, engineering modifications are necessary. However, conventional methods such as centrifugation, ultrasound, and genetic engineering are often time-consuming and can damage the structural integrity of EVs. Bioorthogonal click chemistry offers unique advantages in EV engineering, particularly through copper-free click chemistry, which primarily includes strain-promoted azide-alkyne cycloaddition (SPAAC) and inverse electron-demand Diels-Alder (iEDDA) reactions. These methods avoid the potential toxicity associated with metal catalysts. This innovative approach provides controllability, specificity, and targeting capability, allowing for rapid reactions while minimizing interference with other biochemical processes <em>in vivo</em>.</span></p>
<p><span style="font-size: 15px;">To achieve bioorthogonal reactions between EVs and biological systems, engineering modifications are primarily achieved through three biological labeling methods: chemical cross-linking and immunoaffinity, membrane insertion, and metabolic labeling. Immunoaffinity methods, which rely on EV surface proteins and antibodies/aptamers, provide high specificity but are limited by high separation costs and low yields. In contrast, membrane insertion naturally embeds lipids or lipid-mimicking molecules into the EV membrane. While membrane insertion is more broadly applicable and cost-effective, it tends to have relatively lower specificity. Metabolic engineering enables the natural modification of cell surfaces with sugars, lipids, and amino acids containing bioorthogonal functional groups (such as azides, alkynes, and aldehydes) through metabolic activities. Among these methods, metabolic engineering ensures high specificity with minimal disruption to EV integrity, facilitating <em>in vivo</em> applications.</span></p>
<p><span style="font-size: 15px;"><img decoding="async" class="aligncenter  wp-image-397" src="http://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/11/2-scaled.jpg" alt="" width="608" height="645" srcset="https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/11/2-scaled.jpg 2412w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/11/2-283x300.jpg 283w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/11/2-965x1024.jpg 965w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/11/2-768x815.jpg 768w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/11/2-1447x1536.jpg 1447w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/11/2-1930x2048.jpg 1930w" sizes="(max-width: 608px) 100vw, 608px" /></span><span style="font-size: 15px;">First, considering that large-scale production of EVs is a key challenge for clinical approval, the use of magnetic beads, microfluidic chips, and microarray chips allows for orthogonal connections with engineered EVs, enabling the isolation of desired EV populations. This separation approach can reduce heterogeneity and facilitate scalable production.</span></p>
<p><span style="font-size: 15px;"><img decoding="async" class="aligncenter  wp-image-398" src="http://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/11/3.jpg" alt="" width="617" height="487" srcset="https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/11/3.jpg 2500w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/11/3-300x237.jpg 300w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/11/3-1024x808.jpg 1024w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/11/3-768x606.jpg 768w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/11/3-1536x1212.jpg 1536w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/11/3-2048x1616.jpg 2048w" sizes="(max-width: 617px) 100vw, 617px" /></span><span style="font-size: 15px;">Secondly, engineered EV nanoprobe systems enable real-time monitoring of EV distribution, transport, and function within the body. This bioimaging technology utilizes SPAAC reactions to link EVs with fluorescent molecules, offering non-invasive and highly specific imaging that effectively overcomes current limitations in tracking and imaging EVs within cells and tissues.</span></p>
<p><span style="font-size: 15px;">For early cancer diagnosis, click-chemistry-based electrochemical biosensors provide a reliable, convenient, and sensitive method to address the challenge of low exosome concentrations in the body fluids of early-stage disease patients. Despite some limitations, these biosensors have significant clinical potential, offering valuable information for disease diagnosis, particularly in early tumor detection and prognosis monitoring.</span></p>
<p><span style="font-size: 15px;">Finally, a major bottleneck in EV-based therapeutic approaches is limited targeting capability. Bioorthogonal chemistry not only extends the diagnostic capabilities of EVs but also enhances their targeting specificity. Through drug multifunctionalization or glycan metabolic engineering, EV drug delivery systems can be used to treat various diseases, including cancer, arthritis, ischemic stroke, and heart disease. In recent years, EV drug delivery has expanded from small molecules to nanozymes, peptides, and cells, enabling EVs to deliver drugs with active or passive targeting abilities. However, the effectiveness of ligand-targeting strategies is limited by the availability and heterogeneous distribution of receptors within tumor cells. Fortunately, bioorthogonal glycan metabolic engineering broadens orthogonal targeting by engineering functionalized glycoproteins at tumor sites, thus improving <em>in vivo</em> therapeutic efficacy. This method allows for precise labeling of tumors and promotes orthogonal drug-tumor binding through click reactions. This interaction inhibits the formation of tumor-derived exosomes (TDEs), prevents their uptake by liver Kupffer cells, and disrupts communication with distant tumors, effectively suppressing metastasis. This highlights the potential of click chemistry in anti-metastasis strategies and targeted EV-based therapies.</span></p>
<p><span style="font-size: 15px;"><img decoding="async" loading="lazy" class="aligncenter  wp-image-399" src="http://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/11/4.jpg" alt="" width="616" height="411" srcset="https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/11/4.jpg 2500w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/11/4-300x200.jpg 300w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/11/4-1024x683.jpg 1024w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/11/4-768x512.jpg 768w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/11/4-1536x1024.jpg 1536w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/11/4-2048x1366.jpg 2048w" sizes="(max-width: 616px) 100vw, 616px" /></span><span style="font-size: 15px;">In summary, bioorthogonal labeling of vesicles holds extensive potential in applications such as EV separation, bioimaging, and targeted therapy, providing essential tools for EV-related research across fields from chemical biology to drug delivery. However, the application of bioorthogonal labeling faces several challenges and limitations, such as potential vascular damage from intratumoral Ac4ManNAz injections, azidosugar leakage, or inconsistent labeling. Enhancing labeling efficiency for tumors or EVs may be achieved by optimizing the chemical structure of natural molecule derivatives, such as adjusting the acyl side chain length in sialic acid analogs, developing Ac4ManAz that responds to tumor microenvironments, or constructing bioresponsive disulfide self-assembling entities.</span></p>
<p><span style="font-size: 15px;">To advance clinical applications, an in-depth understanding of the metabolic pathways involved in bioorthogonal labeling is essential for evaluating <em>in vivo</em> behavior. Additionally, the commercialization of bioorthogonal-functionalized EVs requires standardized purification processes and quality control measures.</span></p>
<p><span style="font-size: 15px;"><strong> </strong></span></p>
<p><span style="font-size: 15px;"><strong>Reference:</strong></span></p>
<p><span style="font-size: 15px;">Fei, Zhengyue et al. &#8220;Engineeringextracellular vesicles for diagnosis and therapy.&#8221; Trends in pharmacological sciences vol. 45,10 (2024): 931-940. doi:10.1016/j.tips.2024.08.007</span></p>
<p><span style="font-size: 15px;"><strong>Related Services:</strong></span></p>
<p><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/exosome/exosome-engineering-services.htm">Exosome Engineering Services</a></span></p>
<p><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/exosome/cargo-loading-into-exosomes.htm">Exosome Cargo Loading Services</a></span></p>
<p><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/exosome/stem-cell-derived-exosomes.htm">Stem Cell-derived Exosome Applications</a></span></p>
]]></content:encoded>
					
		
		
			</item>
		<item>
		<title>Tumor-Derived Small Extracellular Vesicles as Barriers to Drug Delivery</title>
		<link>https://www.creative-biolabs.com/blog/exosome/exosome-therapy/tumor-derived-small-extracellular-vesicles-as-barriers-to-drug-delivery/</link>
		
		<dc:creator><![CDATA[biolabs]]></dc:creator>
		<pubDate>Sat, 28 Sep 2024 09:36:15 +0000</pubDate>
				<category><![CDATA[Exosome Therapy]]></category>
		<guid isPermaLink="false">https://www.creative-biolabs.com/blog/exosome/?p=377</guid>

					<description><![CDATA[On September 2, 2024, Nature Materials published a study titled &#8220;Tumour-derived small extracellular vesicles act as a barrier to therapeutic nanoparticle delivery.&#8221; This research challenges traditional views by revealing that tumor-secreted exosomes<a class="moretag" href="https://www.creative-biolabs.com/blog/exosome/exosome-therapy/tumor-derived-small-extracellular-vesicles-as-barriers-to-drug-delivery/">Read More...</a>]]></description>
										<content:encoded><![CDATA[<p><span style="font-size: 15px;">On September 2, 2024, Nature Materials published a study titled &#8220;Tumour-derived small extracellular vesicles act as a barrier to therapeutic nanoparticle delivery.&#8221;</span></p>
<p><img decoding="async" loading="lazy" class=" wp-image-378 aligncenter" src="http://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/10/1.png" alt="" width="598" height="369" srcset="https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/10/1.png 851w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/10/1-300x185.png 300w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/10/1-768x474.png 768w" sizes="(max-width: 598px) 100vw, 598px" /></p>
<p><span style="font-size: 15px;">This research challenges traditional views by revealing that tumor-secreted exosomes serve as a biological barrier, playing a key role in cancer resistance to therapy. These exosomes bind to therapeutic drugs, diverting them away from tumors and toward degradation in Kupffer cells in the liver, thereby reducing drug accumulation in tumors and diminishing therapeutic effectiveness.</span></p>
<p style="text-align: center;"><img decoding="async" loading="lazy" class="aligncenter wp-image-379" src="http://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/10/2.png" alt="" width="641" height="227" srcset="https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/10/2.png 1298w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/10/2-300x106.png 300w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/10/2-1024x363.png 1024w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/10/2-768x272.png 768w" sizes="(max-width: 641px) 100vw, 641px" /><span style="font-size: 12px;">Figure: Illustration of the defense mechanism mediated by tumor-secreted small extracellular vesicles (sEVs).</span></p>
<p><span style="font-size: 15px;">Nanoparticle drug delivery systems have been widely applied in clinical settings, but a core challenge is how to effectively deliver a sufficient amount of nanoparticles to tumor sites to achieve optimal therapeutic effects. Although various strategies have been developed—including optimizing the size, shape, and surface chemistry of nanoparticles, as well as enhancing their accumulation in tumors through the enhanced permeability and retention (EPR) effect or ligand-targeting mechanisms— research has shown that only a very small fraction of intravenously injected nanoparticles ultimately reach and accumulate in solid tumors. This inefficiency significantly limits the potential of nanoparticles in tumor treatment.</span></p>
<p><span style="font-size: 15px;">In recent years, researchers have begun to focus on certain characteristics of the tumor microenvironment, such as the dense extracellular matrix, solid stress, and abnormal vascular structures, which significantly impact nanoparticle accumulation in tumors. Despite tremendous efforts to overcome these obstacles, progress remains limited, primarily due to the many unknowns surrounding the mechanisms of drug delivery to tumor tissue. Small extracellular vesicles (sEVs) are a class of small vesicles secreted by cells and found in various tissue environments, including tumors. Studies have shown that tumor cells are one of the primary sources of sEVs, which are typically present at higher concentrations in the tumor microenvironment than in healthy tissue. However, the physicochemical significance of the high concentration of exosomes at tumor sites has long been overlooked.</span></p>
<p><span style="font-size: 15px;">Through a series of experiments, the paper reveals how tumor-derived sEVs hinder nanoparticle accumulation in tumor tissues. First, the researchers validated this hypothesis in a mouse model. By knocking out the Rab27a gene using CRISPR-Cas9 technology, the study demonstrated that Rab27a knockout significantly reduced sEV secretion from tumor cells in mice, directly leading to a substantial increase in nanoparticle accumulation in the tumor. Moreover, the experiments found that Rab27a gene knockout not only reduced sEV accumulation in liver Kupffer cells but also increased nanoparticle uptake by tumor cells and tumor-infiltrating immune cells.</span></p>
<p><span style="font-size: 15px;">A key finding of the study is that sEVs can bind to nanoparticles and transport them to Kupffer cells in the liver for degradation through physical forces such as van der Waals forces, thereby reducing nanoparticle accumulation in tumors. The researchers observed that the binding of sEVs to nanoparticles increased the size of the complexes, which may further affect their permeability and accumulation in tumors. However, experimental results indicated that the inhibition of nanoparticle uptake by sEVs was not solely due to the size increase; it also involved molecular-level interactions. For example, by using antibodies to block the adhesion molecule ICAM-1 on the surface of sEVs, the researchers further confirmed the role of ICAM-1 in the interaction between sEVs and nanoparticles and their transport to Kupffer cells. This molecular mechanism highlights the active role of tumors in resisting treatment strategies.</span></p>
<p><span style="font-size: 15px;">Next, the researchers explored the possibility that inhibiting the secretion of sEVs could reduce the levels of sEVs that bind to nanoparticles, thereby significantly enhancing nanoparticle delivery efficiency and improving their therapeutic effectiveness in tumor treatments. Notably, they proposed combining Rab27a knockout with the co-delivery of therapeutic mRNA, such as Pten or Sting mRNA, which showed significant antitumor effects in mouse models without causing notable organ toxicity. The researchers further examined the applicability of the sEV barrier effect in other therapeutic methods. The results indicated that sEVs not only hindered the delivery of organic nanoparticles (such as liposomes and PLGA nanoparticles) but also had significant effects on inorganic nanoparticles (such as nanoparticles and silica nanoparticles) and other tumor therapies, including oncolytic virus therapy and antibody therapy. This discovery broadens the scope of sEVs as therapeutic barriers, suggesting that targeted treatment against sEVs could be an effective strategy for enhancing the efficacy of various tumor therapies.</span></p>
<p><span style="font-size: 15px;">Overall, this paper reveals how tumor-derived sEVs hinder nanoparticle delivery through detailed experiments and in-depth mechanistic analysis. It proposes potential strategies to improve the therapeutic outcomes of nanoparticles in tumor treatments by disrupting this barrier. This research not only enhances the understanding of the role of sEVs in the tumor microenvironment but also offers new insights for future nanodrug development. The study holds significant implications for various tumor therapies, and future research may further explore effective methods to overcome the sEV barrier, investigate the role of sEVs in other types of tumors, and examine their interactions with different treatment methods, thereby advancing the success of tumor therapies.</span></p>
<p>&nbsp;</p>
<p><span style="font-size: 15px;"><strong>Reference:</strong></span></p>
<p><span style="font-size: 12px;">Gong, Ningqiang et al. &#8220;Tumour-derived small extracellular vesicles act as a barrier to therapeutic nanoparticle delivery.&#8221; Nature materials, 10.1038/s41563-024-01961-6. 2 Sep. 2024, doi:10.1038/s41563-024-01961-6</span></p>
<p><span style="font-size: 15px;"><strong>Related Services:</strong></span></p>
<p><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/exosome/nanoparticle-tracking-analysis-based-exosome-characterization.htm">Nanoparticle Tracking Analysis-based Exosome Characterization</a></span></p>
<p><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/exosome/lipidsync-exosomes-development-services.htm">LipidSync Exosomes Development Services</a></span></p>
<p><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/exosome/cargo-loading-into-exosomes.htm">Exosome Cargo Loading Services</a></span></p>
]]></content:encoded>
					
		
		
			</item>
		<item>
		<title>The Biology and Function of Extracellular Vesicles in Immunity</title>
		<link>https://www.creative-biolabs.com/blog/exosome/exosome-review/the-biology-and-function-of-extracellular-vesicles-in-immunity/</link>
		
		<dc:creator><![CDATA[biolabs]]></dc:creator>
		<pubDate>Wed, 28 Aug 2024 09:33:49 +0000</pubDate>
				<category><![CDATA[Exosome Review]]></category>
		<guid isPermaLink="false">https://www.creative-biolabs.com/blog/exosome/?p=364</guid>

					<description><![CDATA[Extracellular vesicles (EVs), including exosomes, encapsulate DNA, RNA, and proteins within a phospholipid bilayer. These vesicles deliver their lumenal cargo to the cytoplasm of recipient cells, influencing immune cell function. This impact<a class="moretag" href="https://www.creative-biolabs.com/blog/exosome/exosome-review/the-biology-and-function-of-extracellular-vesicles-in-immunity/">Read More...</a>]]></description>
										<content:encoded><![CDATA[<p><span style="font-size: 15px;">Extracellular vesicles (EVs), including exosomes, encapsulate DNA, RNA, and proteins within a phospholipid bilayer. These vesicles deliver their lumenal cargo to the cytoplasm of recipient cells, influencing immune cell function. This impact is partly due to the intersection of EV biogenesis with antigen processing and presentation pathways. EVs derived from activated immune cells can increase the frequency of immune synapses on recipient cells, regulating both local and systemic immunity in various conditions, such as inflammation, autoimmunity, organ fibrosis, cancer, and infection. Both natural and engineered EVs have demonstrated the ability to modulate innate and adaptive immunity and are currently being explored in clinical trials. EVs may be integral to a well-functioning immune system and hold promise as immunotherapeutic agents. Recently, Raghu Kalluri, a leading expert on exosomes, published a review in the journal Immunity, summarizing the biology and function of extracellular vesicles in the immune system.</span></p>
<p><img decoding="async" loading="lazy" class="aligncenter  wp-image-365" src="http://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/09/1.jpg" alt="" width="639" height="146" srcset="https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/09/1.jpg 964w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/09/1-300x69.jpg 300w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/09/1-768x176.jpg 768w" sizes="(max-width: 639px) 100vw, 639px" /></p>
<p><span style="font-size: 15px;">Early functional studies suggested that EVs, containing DNA, RNA, proteins, and lipids, might play a role in antigen presentation and adaptive immune responses. Such initial observations opened up an emerging field of research focused on the role of EVs in immune responses and overall immunity. The heterogeneous nature of EVs, their biogenesis, and their putative roles have become a central focus in multiple biomedical fields as researchers work to elucidate their significance in both physiological and pathological responses. All prokaryotic and eukaryotic cells secrete EVs that participate in complex biological signaling networks within recipient cells. The surface ligands and receptors on EVs reflect their cellular origin, with many cellular components being found within EVs. Some components are more commonly found in EVs and exosomes—a subtype of EVs originating from the endocytic pathway and typically ranging in size from 40 to approximately 180 nm.</span></p>
<p style="text-align: center;"><img decoding="async" loading="lazy" class="aligncenter  wp-image-369" src="http://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/09/2.jpg" alt="" width="633" height="494" srcset="https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/09/2.jpg 1310w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/09/2-300x234.jpg 300w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/09/2-1024x798.jpg 1024w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/09/2-768x599.jpg 768w" sizes="(max-width: 633px) 100vw, 633px" /><span style="font-size: 12px;">EV structure, biogenesis, and heterogeneity, relevant to antigen processing and presentation</span></p>
<p><span style="font-size: 15px;">The biogenesis of EVs and exosomes may intersect with multiple pathways that regulate their content composition. EVs exhibit heterogeneity in their biogenesis, size, content, and structure.</span></p>
<p><span style="font-size: 15px;"><strong>The role of EVs in immunity: from early discoveries of antigen presentation to inducers of complex intracellular signaling networks</strong></span></p>
<p><span style="font-size: 15px;">EVs have important functions in antigen presentation and adaptive immune responses, extending beyond their initial characterization as vehicles shedding membrane proteins in reticulocyte maturation. EVs released from dendritic cells (DCs) loaded with tumor peptides can directly stimulate T cells through MHC class II peptide complexes and exhibit antitumor activity in mice. This demonstrates the role of EVs in cross-priming, which stimulates the generation of activated CD8+ T cells from naive CD8+ T cells. EVs can also facilitate the exchange of MHC class II antigen complexes between DCs to activate T cells, as well as influence the intercellular programming of DCs by mediating the exchange of miRNA between cells, highlighting their complexity in signaling. EVs derived from DCs and B cells can stimulate T cell proliferation and cytokine production <em>in vitro</em>, laying the foundation for the potential application of EVs as vaccines by directly or indirectly loading them with antigenic peptides. <em>In vivo</em>, EV exchange between DCs may enhance T cell activation during transplant rejection. Additionally, small DC-derived EVs may deliver different polarization signals to T cells depending on the maturation state of the DCs, compared with larger ones, emphasizing the functional heterogeneity of EVs and the impact of cell state on their function. Not only do DCs secrete functional EVs, but their differentiation <em>in vitro</em> is also influenced by cancer cell-derived EVs, underscoring the dynamic and complex regulatory role of EVs in immune responses. In recent years, research has unveiled the role of EVs in infectious diseases (such as COVID-19), microbiota regulation, aberrant immune responses, and cancer development, driving the development of engineered EVs as immunotherapeutic agents. Given the potential role of EVs in antigen presentation, especially in T cell cross-priming, EVs may play an important role in the development of antiviral vaccines and anticancer strategies. Crucially, the roles of EVs as immunomodulators are functionally diverse and reflect the dynamic contributions of their microenvironment and cellular origin. For example, EVs are involved in T cell cross-priming and cross-tolerance, can either enhance or limit viral immunity, promote or inhibit anti-tumor immune responses, regulate or dysregulate the microbiota, and exacerbate or reduce inflammatory responses. The bimodal functions of EVs represent their diverse cellular origins and dynamic microenvironments, suggesting their pivotal role in the multidirectional calibration of immune signaling.</span></p>
<p style="text-align: center;"><span style="font-size: 12px;"><img decoding="async" loading="lazy" class="aligncenter  wp-image-366" src="http://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/09/3-scaled.jpg" alt="" width="646" height="1056" srcset="https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/09/3-scaled.jpg 1566w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/09/3-184x300.jpg 184w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/09/3-626x1024.jpg 626w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/09/3-768x1255.jpg 768w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/09/3-940x1536.jpg 940w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/09/3-1253x2048.jpg 1253w" sizes="(max-width: 646px) 100vw, 646px" />EVs from different cell types within the ecosystem are responsible for coordinating antigen presentation and regulating immune responses, thereby influencing tissue damage and disease states.</span></p>
<p><span style="font-size: 15px;"><strong>EVs can modulate the immune system: contextual production of EVs shapes bimodal immune responses</strong></span></p>
<p><span style="font-size: 15px;">EVs are generated by all immune and tissue-resident cells, playing key roles in influencing multiple biological pathways associated with tissue injury, inflammation, autoimmunity, infection, and cancer. In different pathological contexts, EVs produced by fibroblasts, vascular endothelial cells, lymphatic endothelial cells, B cells, T cells, natural killer (NK) cells, dendritic cells (DCs), macrophages, and neutrophils may work in a coordinated manner to provide both positive and negative signals.</span></p>
<p style="text-align: center;"><img decoding="async" loading="lazy" class="aligncenter  wp-image-367" src="http://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/09/4-scaled.jpg" alt="" width="634" height="359" srcset="https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/09/4-scaled.jpg 2560w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/09/4-300x170.jpg 300w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/09/4-1024x579.jpg 1024w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/09/4-768x434.jpg 768w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/09/4-1536x869.jpg 1536w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/09/4-2048x1158.jpg 2048w" sizes="(max-width: 634px) 100vw, 634px" /><span style="font-size: 12px;">Many different cell types, including immune cells, are involved in generating EVs that reflect their biological phenotype and provide positive and negative signals to influence tissue fate</span></p>
<p><span style="font-size: 15px;">The environment of EVs influences tissue homeostasis and diverse immune signaling to regulate tissue injury, inflammation, autoimmunity, infection, and cancer. EVs may functionally protect tissues or promote disease depending on the context, reflecting the cellular and molecular signals received by their cells of origin. The ultimate outcome of EVs in tissues may depend on how these diverse activities are balanced.</span></p>
<p><span style="font-size: 15px;">To successfully initiate and execute an effective adaptive immune response, coordinated interactions between dendritic cells (DCs), T cells, B cells, and antigenic targets need to occur appropriately and in sequence. Different types of leukocytes must interact in lymph nodes (LNs), secondary lymphoid organs (SLOs), and peripheral tissues in response to a single antigenic stimulus. All participating cells must generally be in the same location so they can coordinate their interactions and form effective immune synapses. For example, successful activation of naive T cells by antigen-presenting DCs may require several specific immune synapses, a requirement that may not be met by incidental contact between the two cells alone. Therefore, it is conceivable that EVs and exosomes serve as important alternatives to promote the rapid formation of multiple additional immune synapses to support an orderly immune response. Conversely, the spatiotemporal organization within SLOs is essential not only to initiate immunity but also to tailor the type of response generated. This EV-mediated immune modulation (EMIM) may be an additional branch of the immune system for the rapid and systemic dissemination of immunity.</span></p>
<p style="text-align: center;"><img decoding="async" loading="lazy" class="aligncenter  wp-image-368" src="http://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/09/5-scaled.jpg" alt="" width="625" height="352" srcset="https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/09/5-scaled.jpg 2560w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/09/5-300x169.jpg 300w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/09/5-1024x576.jpg 1024w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/09/5-768x432.jpg 768w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/09/5-1536x864.jpg 1536w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/09/5-2048x1153.jpg 2048w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/09/5-1600x900.jpg 1600w" sizes="(max-width: 625px) 100vw, 625px" /><span style="font-size: 12px;">Potential contribution of EVs in regulating systemic immune responses</span></p>
<p><span style="font-size: 15px;">Recent evidence suggests that EVs may represent an underappreciated branch of the immune system, capable of rapidly amplifying immune signals systemically without requiring cell-to-cell proximity and direct interactions. EVs may fulfille these requirements, as shown in this schematic. EVs released by DCs, B cells, CD4+ T cells, and CD8+ T cells can mediate interactions that promote immunity and weaken target cells. This system, regulated by EVs, is termed &#8220;EV-mediated immunomodulation&#8221; (EMIM) and may represent a new branch of the immune response.</span></p>
<p><span style="font-size: 15px;">In addition, the review introduces the following points:</span></p>
<ul>
<li><span style="font-size: 15px;">EVs regulate the metabolic program of immune cells.</span></li>
<li><span style="font-size: 15px;">EVs can be exploited by pathogens but can also be produced to defend against them.</span></li>
<li><span style="font-size: 15px;">EVs serve as viral baits and have potential use in vaccine development.</span></li>
<li><span style="font-size: 15px;">EVs regulate the microbiota.</span></li>
<li><span style="font-size: 15px;">EVs are involved in abnormal immune responses, such as chronic inflammation and autoimmunity.</span></li>
<li><span style="font-size: 15px;">EVs play a role in tumor immunotherapy</span></li>
</ul>
<p><span style="font-size: 15px;">The role of EVs in orchestrating complex immune responses is gaining increasing attention, with numerous studies demonstrating that their cargo selection and effects on recipient cells are dynamic and influenced by their microenvironment. The dual functions of EVs in inflammatory responses, immune cell signaling, and immunity are primarily derived from <em>in vitro</em> studies or observations of exogenous EVs. These observations must be validated using appropriate and relevant <em>in vivo</em> models to determine their rate-limiting functions in both physiological and pathological contexts. Questions regarding the dosage of EVs in immune responses complicate the physiological relevance of many studies, especially when considering the limitations of current isolation methods. Nonetheless, the consistent observation of EV effects on the regulation of innate and adaptive immune responses supports their function as regulators of the immune system. Future studies should consider using relevant genetic models with <em>in vivo</em> generation of immunomodulatory active EVs to study them at natural and physiological concentrations.</span></p>
<p><span style="font-size: 15px;">EVs may act as &#8220;first responders&#8221; in response to tissue damage, serving as sensors, initiators, and controllers of immune responses. The context-dependency and dynamic evolution of their contents make EVs unique immunomodulatory components in the body, capable of refining the direction of immune responses—whether enhancing or suppressing them. With the application of optimized isolation techniques with single vesicle resolution, the more precise effects of EVs on immune system cells will be recognized.</span></p>
<p><span style="font-size: 15px;">Despite the challenges of studying natural EVs, the therapeutic potential of engineered EVs remains attractive, as they can be designed to either suppress or stimulate immune responses. Clinical studies of EVs involve challenges such as the scalability and stability of clinical products, the selection of appropriate cell sources, and the impact of engineering changes on safety. However, EVs may become key players in immune responses and regulation in both health and disease, and they hold significant therapeutic potential.</span></p>
<p>&nbsp;</p>
<p><span style="font-size: 15px;"><strong>Reference:</strong></span></p>
<p><span style="font-size: 12px;">Kalluri, Raghu. &#8220;The biology and function of extracellular vesicles in immune response and immunity.&#8221; Immunity vol. 57,8 (2024): 1752-1768. doi:10.1016/j.immuni.2024.07.009</span></p>
<p>&nbsp;</p>
<p><span style="font-size: 15px;"><strong>Related Services:</strong></span></p>
<p><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/exosome/exosome-lipidomics-metabolomics-services.htm">Exosome Lipidomics &amp; Metabolomics Services</a></span></p>
<p><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/exosome/category-exosome-release-modulation-reagents-1397.htm">Exosome Release Modulation Reagents</a></span></p>
<p><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/exosome/exosome-communication-between-tissues-advance-summary.htm">Exosome Communication between Tissues</a></span></p>
]]></content:encoded>
					
		
		
			</item>
		<item>
		<title>Immunogenicity of Extracellular Vesicles</title>
		<link>https://www.creative-biolabs.com/blog/exosome/exosome-review/immunogenicity-of-extracellular-vesicles/</link>
		
		<dc:creator><![CDATA[biolabs]]></dc:creator>
		<pubDate>Sun, 28 Jul 2024 09:54:38 +0000</pubDate>
				<category><![CDATA[Exosome Review]]></category>
		<guid isPermaLink="false">https://www.creative-biolabs.com/blog/exosome/?p=342</guid>

					<description><![CDATA[Extracellular vesicles (EVs), including exosomes, are cell-derived nano or micrometer-sized monolayer or multilayer membrane structures. EVs contain bioactive cargoes such as nucleic acids, lipids, proteins, and carbohydrates, and play a key role<a class="moretag" href="https://www.creative-biolabs.com/blog/exosome/exosome-review/immunogenicity-of-extracellular-vesicles/">Read More...</a>]]></description>
										<content:encoded><![CDATA[<p><span style="font-size: 15px;">Extracellular vesicles (EVs), including exosomes, are cell-derived nano or micrometer-sized monolayer or multilayer membrane structures. EVs contain bioactive cargoes such as nucleic acids, lipids, proteins, and carbohydrates, and play a key role in intercellular communication. The bioactive cargoes of EVs make them promising therapeutic agents for various diseases. In addition, the surface of EVs mediates <em>in vivo</em> transport and site-specific delivery, allowing EVs to be used as drug delivery systems for small molecules and biopharmaceuticals.</span></p>
<p><span style="font-size: 15px;">An ideal EV-based therapeutic and/or drug delivery system should possess the following properties: i) maintain structural and biomolecular integrity before administration and when exposed to the biological environment, and ii) enable targeted delivery, including site-specific interactions at the organ, cellular, and subcellular levels. For synthetic nanoparticles, site-specific delivery generally improves with prolonged circulation time. However, prolonged circulation of cytotoxic drugs may lead to leukocyte damage, resulting in hematotoxicity. Preclinical studies have shown that intravenously injected EVs are cleared from the blood circulation within minutes. The necessity for EVs to persist in the bloodstream is unclear. It is possible that EVs, due to their more complex surfaces compared to clinically approved synthetic nanoparticles, may exhibit superior immune evasion and targeting properties. In this case, EVs may require shorter circulation times to interact efficiently with their targets.</span></p>
<p><span style="font-size: 15px;">EVs have similar bioactive properties to the cells from which they are derived, but offer several advantages over cell therapies, including improved safety due to the elimination of the risk of malignant growth and vascular occlusion. In addition, EVs are easier to handle and store than cells. Several EV clinical trials have been completed and more are underway to treat various diseases. Encouragingly, neither autologous nor allogeneic EV trials have shown toxicity. Furthermore, plasma transfusions, which are frequently performed in the clinic, result in the transfer of trillions of EVs and generally do not result in adverse events, further indicating the biocompatibility of allogeneic EVs. Animal studies have also shown that the administration of human EVs does not induce (immuno)toxicity.</span></p>
<p><span style="font-size: 15px;">Although EV therapeutics and drug delivery platforms have shown good safety profiles in preclinical and clinical studies, the unexpected immunogenicity of EVs (beyond the absence of immunotoxicity) remains largely unexplored. This Perspective focuses on adverse immune interactions. Readers are referred to other literature for studies that intentionally induced EV immunogenicity, such as EV-based vaccines and immunotherapy.</span></p>
<p><img decoding="async" loading="lazy" class="size-full wp-image-343 aligncenter" src="http://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/08/1.jpg" alt="" width="776" height="285" srcset="https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/08/1.jpg 776w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/08/1-300x110.jpg 300w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/08/1-768x282.jpg 768w" sizes="(max-width: 776px) 100vw, 776px" /></p>
<p><span style="font-size: 15px;">Compared with autologous EVs, xenogeneic and allogeneic EVs may show enhanced clearance by the innate and adaptive immune systems, especially after repeated administration. In the case of the adaptive immune system, EV-associated donor antigens bind to major histocompatibility complex (MHC) molecules, triggering an immune response. Notably, MHC molecules are enriched on EVs compared with the cells of origin. Independently of the adaptive immune system, the mononuclear phagocyte system can recognize xenogeneic and allogeneic EVs as foreign, for example, due to polymorphisms in self-recognition ligand-receptor pairs on macrophages. Whether this ability of the innate immune system to immediately discriminate between self and xenogeneic/allogeneic products applies to EVs remains unknown. Studies over the past decade have also shown that phagocytes can develop immunological memory to foreign biomolecules, which is thought to require an initial stimulation by the adaptive immune system.</span></p>
<p><span style="font-size: 15px;">Although autologous EVs face less immune clearance, they encounter considerable challenges, such as high production costs and labor-intensive operations. Additionally, the therapeutic and drug delivery effects of autologous EVs may vary greatly due to the heterogeneity of EVs between individuals and across healthy/disease conditions. Screening for the best allogeneic donors and pooling donor EVs can reduce batch-to-batch variability. Therefore, allogeneic EVs have the potential to reduce manufacturing costs, improve batch consistency, and ensure efficacy. This article critically evaluates the potential immunogenicity of EVs and discusses emerging strategies to mitigate adverse immune recognition of EVs for next-generation therapeutics and drug delivery systems.</span></p>
<p><span style="font-size: 15px;">The immunogenicity of EVs may be affected by multiple factors, including origin (source and biogenesis), size, endogenous/exogenous content, production and storage methods, dose, infusion rate, and biomolecular coron.</span></p>
<p style="text-align: center;"><img decoding="async" loading="lazy" class=" wp-image-344 aligncenter" src="http://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/08/2.jpg" alt="" width="626" height="648" srcset="https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/08/2.jpg 1000w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/08/2-290x300.jpg 290w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/08/2-989x1024.jpg 989w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/08/2-768x795.jpg 768w" sizes="(max-width: 626px) 100vw, 626px" /><span style="font-size: 12px;">Examples of the biogenesis of EVs and factors that may affect the immunogenicity of EVs</span></p>
<p><span style="font-size: 15px;"><strong>1.1 Sources of EVs</strong></span></p>
<p><span style="font-size: 15px;">In general, transplanted cells can only successfully evade immune recognition if they are fully genetically and epigenetically identical to the recipient. However, achieving this consistency is often challenging. Stem cells (such as embryonic stem cells, mesenchymal stromal cells (MSCs), and adipose-derived stem cells) have low immunogenicity and are able to release EVs that play a key role in intercellular communication and immune suppression. Cancer cells also evade immune surveillance, and their derived EVs can maintain immune evasion properties and promote the formation of an immunosuppressive environment. Understanding these interactions is important for designing therapeutic EVs with immune evasion properties.</span></p>
<p><span style="font-size: 15px;"><strong>1.2 Size of EVs</strong></span></p>
<p><span style="font-size: 15px;">EVs vary widely in size, with different types of EVs displaying distinct size characteristics. Exosomes (30-200 nm), ectosomes (0.1-1 µm), and apoptotic bodies (1-5 µm) overlap in size, affecting their interactions with immune cells. Small EVs show better delivery in tumors and inflammatory tissues, while larger EVs exhibit different accumulation patterns in specific organs. The balance between size, clearance rate, and target cell uptake rate is key to developing effective EV therapeutics and drug delivery systems.</span></p>
<p><span style="font-size: 15px;"><strong>1.3 Surface Composition of EVs</strong></span></p>
<p><span style="font-size: 15px;">Specific surface components can either camouflage EVs from the immune system or accelerate their recognition. EV surface proteins (such as tetraspanins, lectins, and integrins) play a key role in immune cell interactions through ligand-receptor mechanisms. Advances in engineering technologies have made it possible to couple or express a variety of &#8220;don&#8217;t eat me&#8221; signaling molecules (such as CD47, CD55, CD59, and CD200) on the surface of EV membranes to overcome phagocytic clearance. The most widely studied &#8220;don&#8217;t eat me&#8221; receptor is the signal regulatory protein α (SIRPα) on macrophages, which specifically recognizes the widely expressed transmembrane protein CD47. CD47 binds to SIRPα on macrophages and inhibits macrophage-mediated phagocytosis. CD47 is present on various EVs and reduces clearance by the mononuclear phagocyte system.</span></p>
<p><span style="font-size: 15px;">In addition, efficient delivery of EVs also requires evading recognition by other immune cells, including natural killer (NK) cells and T cells. MHC-I molecules are widely expressed on the surface of all nucleated cells and play a key role in presenting endogenous antigens. During the production process of EVs, MHC-I molecules are inevitably integrated into the vesicle membrane. Gene editing technology enables selective targeting and knock out of the beta2-microglobulin (B2M) gene, thereby effectively reducing the expression of MHC-I molecules and making the immunogenicity of such EVs significantly lower compared to EVs containing intact MHC-I molecules.</span></p>
<p style="text-align: center;"><img decoding="async" loading="lazy" class="wp-image-345 aligncenter" src="http://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/08/3.jpg" alt="" width="622" height="481" srcset="https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/08/3.jpg 667w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/08/3-300x232.jpg 300w" sizes="(max-width: 622px) 100vw, 622px" /><span style="font-size: 12px;">EV biomolecular surface composition and factors affecting immunogenicity. a) EV biomolecular surface composition. b) EV surface CD47-mediated “don’t eat me” pathway. c) EV surface MHC-1/PD-L1-mediated immune tolerance. d) EV surface glycoconjugate-mediated receptor cell uptake.</span></p>
<p><span style="font-size: 15px;">Non-classical MHC-I molecules (such as MHC-E, MHC-F, and MHC-G) can inhibit NK cell activity. In the context of cancer cells, abnormal expression of MHC-G allows the release of EVs containing MHC-G, thereby promoting the establishment of immune tolerance in the host. Immune checkpoint molecules such as programmed death ligand 1 (PD-L1) can inhibit T lymphocyte function. Increasing the expression of PD-L1 on the surface of MSC-derived EVs exhibits immunosuppressive effects on T cells, macrophages, and dendritic cells.</span></p>
<p><span style="font-size: 15px;">Sugars and lipids on the EV membrane are also important signaling molecules that affect EV immunogenicity. The outer membrane surface of EVs is rich in sugars, and its glycoconjugate spectrum plays a key role in cellular uptake and biodistribution. Lipids also play an active role in intercellular communication and immune regulation. For example, lipids in cancer cell-derived EVs can produce immunomodulatory effects, including metabolic remodeling and regulation of immune cell signaling pathways.</span></p>
<p style="text-align: center;"><img decoding="async" loading="lazy" class=" wp-image-346 aligncenter" src="http://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/08/4.jpg" alt="" width="661" height="268" srcset="https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/08/4.jpg 1167w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/08/4-300x122.jpg 300w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/08/4-1024x416.jpg 1024w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/08/4-768x312.jpg 768w" sizes="(max-width: 661px) 100vw, 661px" /><span style="font-size: 12px;">EV surface engineering methods and labeling strategies. a) EV engineering methods, including genetic engineering, chemical engineering, and membrane hybridization. b) EV labeling strategies, including fluorescent, luminescent, and radioactive labeling.</span></p>
<p><span style="font-size: 15px;">Choosing the appropriate engineering method is crucial for achieving optimal expression of biomolecules on the surface of EVs. Common engineering techniques include genetic engineering, chemical engineering, and membrane hybridization. Genetic engineering involves transfecting recombinant DNA into host cells through expression vectors (such as plasmids or lentiviruses) to achieve the expression of the desired protein. Chemical engineering techniques can be divided into non-covalent and covalent modifications. EV membrane hybridization (fusion) combines EV cell membranes with artificial membranes through methods such as physical extrusion, ultrasound, and electroporation. Common EV labeling methods include fluorescence, luminescence, and radioactive labeling, but these methods may affect the function and immunogenicity of EVs.</span></p>
<p><span style="font-size: 15px;"><strong>1.4 Internal Components of EVs</strong></span></p>
<p><span style="font-size: 15px;">In addition to the surface components of EVs, endogenous and exogenous internal cargoes can also show immunomodulatory effects. For example, the circular RNA circNEIL3, which is highly expressed in brain gliomas, is encapsulated in EVs and engulfed by macrophages, resulting in an immunosuppressive phenotype. Various EV engineering methods can be used to load exogenous cargoes inside EVs, but these methods may affect the properties and immunogenicity of the EVs. Indirect loading involves exposing the source cells to the cargo, though loading efficiency is limited. Direct methods for loading internal cargo include ultrasound, extrusion, pore formers, and repeated freeze-thaw cycles, which can temporarily create openings in the membrane. However, studies have shown that ultrasound and extrusion may reduce the activity of enzymes carried by EVs, potentially causing damage or loss of endogenous biomolecules.</span></p>
<p><span style="font-size: 15px;">Besides, source cells can be genetically engineered to express proteins or RNA and load them into the interior of EVs. Compared to physical and chemical loading methods, genetic engineering has less effect on the structural integrity of EVs. Loading efficiency can be improved by fusing the desired biomolecules to internal proteins of EVs. Genetic engineering techniques have also been used to endow EVs with immunomodulatory properties. For example, genetically engineered EVs loaded with CC16 protein have demonstrated anti-inflammatory effects by regulating macrophages and neutrophils in an acute pneumonia mouse model.</span></p>
<p><span style="font-size: 15px;"><strong>1.5 Production and Storage of EVs</strong></span></p>
<p><span style="font-size: 15px;">Production and storage methods can result in varying degrees of EV damage, thus affecting their immunogenicity. For example, the state of the source cells may influence the immunogenicity of EVs. Cellular stress can release EVs containing specific immunomodulatory mediators through stress-induced pathways. Separation methods (such as ultracentrifugation and dead-end filtration) may cause EV aggregation, membrane damage, and biomolecule damage, which could trigger immune responses. Exposed intracellular biomolecules from cells can trigger immune responses, but it is unclear whether exposed internal EV cargoes have a similar effect. Tangential flow filtration can be used as a gentle EV isolation method (controlled shear rate) to reduce EV damage and, thus, mitigate its immunogenicity.</span></p>
<p><span style="font-size: 15px;">Engineering EVs to carry targeting, imaging, and therapeutic agents may also cause EV damage, and these components could trigger immune responses. The extent of contaminants in EV samples may also affect immune responses. For example, hyaluronan, whose effects on the immune system depend on molecular weight, was recently found to be a contaminant in EV samples, with levels varying depending on the EV isolation method. Ultracentrifugation and precipitation kits result in the co-precipitation of numerous protein contaminants, while all size-based EV isolation methods retain protein aggregates, which may affect dosing accuracy or misattribute immunomodulatory effects to EVs. Density gradient ultracentrifugation can be used to increase the purity of EV samples.</span></p>
<p style="text-align: center;"><img decoding="async" loading="lazy" class=" wp-image-347 aligncenter" src="http://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/08/5.jpg" alt="" width="630" height="412" srcset="https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/08/5.jpg 667w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/08/5-300x196.jpg 300w" sizes="(max-width: 630px) 100vw, 630px" /><span style="font-size: 12px;">Examples of EV production and storage methods. Tangential flow filtration causes less EV damage and aggregation than ultracentrifugation, which may mitigate immune recognition. Density gradient ultracentrifugation yields higher purity EVs than ultracentrifugation, which may affect their immunogenicity. Storage methods may affect EV integrity and potential immunogenicity.</span></p>
<p><span style="font-size: 15px;">In clinical practice, immediate use of freshly prepared EVs is often not feasible, making storage a key consideration for the clinical translation of EV therapeutics and drug delivery systems. Typically, EVs can be stored at 4°C for a short period (&lt;48 hours), while long-term storage requires −80°C conditions. However, the potency of EVs generally decreases after storage. Repeated freeze-thaw cycles and prolonged storage can cause EV fusion or aggregation, increase particle size and reduce potency. The lack of cryoprotectants can affect the integrity of EVs, thereby influencing their immunogenicity.</span></p>
<p><span style="font-size: 15px;"><strong>1.6 EV Dosage</strong></span></p>
<p><span style="font-size: 15px;">The dose and route of administration of EVs are key factors affecting their immunogenicity. Different routes of administration (e.g., intravenous, intraperitoneal, and subcutaneous) result in different biodistribution and immune cell exposure patterns. In mouse models, intravenously injected EVs rapidly accumulate in the liver and spleen and are also distributed in the lungs and kidneys. Intraperitoneally injected EVs are better absorbed in adipose tissue than intravenously injected EVs, while subcutaneous and intraperitoneal injections increase EV absorption in the gastrointestinal tract and pancreas.</span></p>
<p><span style="font-size: 15px;"><strong>1.7 EV Infusion Rate</strong></span></p>
<p><span style="font-size: 15px;">Intravenously infused therapeutics and drug delivery systems face the challenge of complement-mediated infusion reactions in clinical translation. For example, the interaction of anti-polyethylene glycol (PEG) antibodies with PEGylated nanoparticles may trigger a complement response, leading to anaphylactic shock. Various therapeutic approaches can cause infusion reactions, which usually occur within minutes of the start of infusion. Premedication and reduced infusion rates can alleviate such reactions. Although EVs may also experience infusion rate reactions, there is currently a lack of evidence as the field is in early clinical development and relies primarily on rodent data.</span></p>
<p><span style="font-size: 15px;"><strong>1.8 The Biomolecular Canopy of EVs</strong></span></p>
<p><span style="font-size: 15px;">Synthetic nanoparticles and EVs are surrounded by a layer of adsorbed biomolecules in biological environments, known as the biomolecular corona. The composition of the corona affects the biological identity of EVs, including immune recognition and clearance. Circulating opsonins (such as complement proteins, immunoglobulins, and coagulation factors) play an important role in mediating the uptake of nanoparticles and EVs by innate immune cells. Complement protein H is abundant in hepatocellular carcinoma EVs, inhibiting the activation of other complement proteins and promoting tumor progression. Reducing the cholesterol content of EV mimics can decrease complement adsorption. Lipoproteins on EVs also affect their interactions with immune cells. Nucleic acids (DNA, RNA) are important components of the EV biomolecular corona and affect immune regulation. Modifying the EV surface can change the corona composition and immune recognition. Removal of the biomolecular corona in donor fluids may affect the immunogenicity of EVs. Future studies should aim to identify EV engineering strategies that help form an ideal biomolecular corona.</span></p>
<p style="text-align: center;"><img decoding="async" loading="lazy" class="wp-image-348 aligncenter" src="http://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/08/6.jpg" alt="" width="624" height="444" srcset="https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/08/6.jpg 667w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/08/6-300x214.jpg 300w" sizes="(max-width: 624px) 100vw, 624px" /><span style="font-size: 12px;">The composition of EV biomolecular surfaces and coronas and their impact on immunity, tissue targeting, and biodistribution</span></p>
<p><span style="font-size: 15px;"><strong>2 Conclusion and Future Outlook</strong></span></p>
<p><span style="font-size: 15px;">The rapidly evolving field of EV therapeutics and drug delivery systems requires a thorough understanding of undesirable immunogenicity, which is critical for developing safe and efficient clinical products. These efforts necessitate interdisciplinary collaborations in immunology, cell biology, and nanomedicine. Although several preclinical and early clinical trials on EVs have demonstrated a remarkable lack of immunotoxicity, immune clearance remains poorly explored, especially in large animal models. Factors contributing to EV immunogenicity include source, size, surface composition, internal contents, production/storage methods, dose, infusion rate, and biomolecular corona. Understanding the impact of these factors on EV immunogenicity has the potential to inform the future development of optimal EV treatments and drug delivery systems. Various strategies to modulate EV immune recognition and clearance, including the addition and removal of EV surface components, have been explored. Future mitigation strategies may rely on improved EV production and storage methods combined with engineered immune evasion surfaces. Several biomolecules on the surface of EVs have been identified to possess either immunostimulatory or immune evasion properties. In the future, omics technologies (proteomics, glycomics, lipidomics, transcriptomics, and metabolomics), combined with functional studies, will be crucial for comprehensively identifying and implementing immune-evading EV surfaces while retaining specific targeting capabilities.</span></p>
<p>&nbsp;</p>
<p><span style="font-size: 15px;"><strong>Reference:</strong></span></p>
<p><span style="font-size: 12px;">Xia, Yutian et al. &#8220;Immunogenicity of Extracellular Vesicles.&#8221; Advanced materials (Deerfield Beach, Fla.), e2403199. 27 Jun. 2024, doi:10.1002/adma.202403199</span></p>
<p><span style="font-size: 15px;"><strong>Related Services:</strong></span></p>
<p><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/exosome/exosome-engineering-services.htm">Exosome Engineering Services</a></span></p>
<p><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/exosome/immune-phage-display-antibody-library-screening-for-exosome.htm">Immune Phage Display Antibody Library Screening for Exosome</a></span></p>
<p><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/exosome/exosome-profiling.htm">Exosome Profiling Services</a></span></p>
]]></content:encoded>
					
		
		
			</item>
		<item>
		<title>Bidirectional Regulation of Extracellular Vesicles and Cellular Epigenetics</title>
		<link>https://www.creative-biolabs.com/blog/exosome/exosome-review/bidirectional-regulation-of-extracellular-vesicles-and-cellular-epigenetics/</link>
		
		<dc:creator><![CDATA[biolabs]]></dc:creator>
		<pubDate>Fri, 28 Jun 2024 09:20:05 +0000</pubDate>
				<category><![CDATA[Exosome Review]]></category>
		<guid isPermaLink="false">https://www.creative-biolabs.com/blog/exosome/?p=330</guid>

					<description><![CDATA[Extracellular vesicles (EVs) are a highly heterogeneous class of membrane vesicles that participate in regulating various biological processes by transporting proteins, lipids, nucleic acids, and metabolites. According to differences in size and<a class="moretag" href="https://www.creative-biolabs.com/blog/exosome/exosome-review/bidirectional-regulation-of-extracellular-vesicles-and-cellular-epigenetics/">Read More...</a>]]></description>
										<content:encoded><![CDATA[<p><span style="font-size: 15px;">Extracellular vesicles (EVs) are a highly heterogeneous class of membrane vesicles that participate in regulating various biological processes by transporting proteins, lipids, nucleic acids, and metabolites. According to differences in size and generation pathways, EVs can be divided into exosomes, microvesicles, apoptotic bodies, and other vesicles (such as migratoria, mitochondrial vesicles, and RAB22A-induced extracellular vesicles, R-EVs, etc.). Exosomes are single-layer vesicles with a diameter of 40-160nm released by the fusion of multivesicular bodies with the plasma membrane, while microvesicles are produced by direct budding outward from the cell membrane. According to the latest guidelines from the International Extracellular Vesicle Association, exosomes and small microvesicles are collectively referred to as small extracellular vesicles (sEVs).</span></p>
<p><span style="font-size: 15px;">Recently, a research team published a review entitled &#8220;Extracellular vesicles as modifiers of epigenomic profiles&#8221; in <em>Trends in Genetics</em> (2024 Jun 5:S0168-9525(24)00109-4). This paper systematically summarizes the latest progress in understanding the interaction between EVs and cellular epigenetic profiles. It emphasizes the significant role of epigenetic-related factors in the biogenesis and secretion of EVs, explains the function of EVs in DNA, RNA and histone modifications, and discusses the clinical application of EVs as diagnostic markers and epigenetic drug delivery carriers.</span></p>
<p><img decoding="async" loading="lazy" class="size-full wp-image-331 aligncenter" src="http://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/07/1.jpg" alt="" width="787" height="242" srcset="https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/07/1.jpg 787w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/07/1-300x92.jpg 300w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/07/1-768x236.jpg 768w" sizes="(max-width: 787px) 100vw, 787px" /></p>
<p><span style="font-size: 15px;"><strong>Epigenetic Factors Involved in Regulating EV Biogenesis</strong></span></p>
<p><span style="font-size: 15px;">In order to accurately transmit information, the biogenesis of small extracellular vesicles (sEVs), cargo sorting, and uptake by recipient cells are precisely regulated by multiple mechanisms, such as histone and DNA modifications, post-translational modifications of non-coding RNAs, and proteins. (Figure 1).</span></p>
<p style="text-align: center;"><img decoding="async" loading="lazy" class=" wp-image-332 aligncenter" src="http://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/07/2-scaled.jpg" alt="" width="638" height="780" srcset="https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/07/2-scaled.jpg 2094w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/07/2-245x300.jpg 245w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/07/2-838x1024.jpg 838w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/07/2-768x939.jpg 768w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/07/2-1257x1536.jpg 1257w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/07/2-1675x2048.jpg 1675w" sizes="(max-width: 638px) 100vw, 638px" /><span style="font-size: 12px;">Figure 1. Epigenetic factors and protein post-translational modifications dynamically regulate EV biogenesis.</span></p>
<p><span style="font-size: 15px;"><strong>The Role of EVs in Epigenetic Remodeling</strong></span></p>
<p><span style="font-size: 15px;">As a critical medium for intercellular communication, EVs are widely involved in various biological processes, including reshaping the epigenetic map of cells. DNA methylation is a common epigenetic modification in eukaryotes and a typical feature of heterochromatin, dynamically regulated by DNA methyltransferases (DNMTs) and Fe (II) and α-ketoglutarate-dependent dioxygenases TETs. RNA methylation, the main type of RNA chemical modification, is added by &#8220;writers,&#8221; removed by &#8220;erasers,&#8221; and recognized by &#8220;readers.&#8221; These proteins coordinate to dynamically regulate the methylation spectrum in cells, maintaining normal cell function. EVs can reshape the methylation patterns of recipient cells by directly transporting &#8220;cargo&#8221; such as mRNA of these proteins or non-coding RNA targeting these proteins, thereby regulating essential biological processes such as replication and apoptosis of recipient cells.</span></p>
<p><span style="font-size: 15px;">Histone modifications, including histone methylation and acetylation, mainly occur at the lysine residues of histone H3 or H4. These modifications are dynamically regulated by protein methyltransferases (HMT), lysine-specific demethylases (KMT), histone acetyltransferase (HAT), and histone deacetylases (HDAC). EV-delivered long noncoding RNAs (lncRNAs) such as UFC1, LNMAT2, and BCYRN1 can recruit HMT to increase histone methylation. In addition, EVs can regulate the expression of &#8220;writers&#8221; and &#8220;erasers&#8221; of histone modifications by delivering miRNA and mRNA, thereby reshaping the epigenetic landscape (Figure 2).</span></p>
<p style="text-align: center;"><img decoding="async" loading="lazy" class=" wp-image-333 aligncenter" src="http://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/07/3.jpg" alt="" width="699" height="530" srcset="https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/07/3.jpg 2500w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/07/3-300x228.jpg 300w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/07/3-1024x777.jpg 1024w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/07/3-768x582.jpg 768w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/07/3-1536x1165.jpg 1536w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/07/3-2048x1553.jpg 2048w" sizes="(max-width: 699px) 100vw, 699px" /><span style="font-size: 12px;">Figure 2. Biological functions of EVs in histone modification</span></p>
<p><span style="font-size: 15px;"><strong>Application of EVs in Disease Diagnosis and Treatment</strong></span></p>
<p><span style="font-size: 15px;">Changes in the epigenetic profile of the mother cells that secrete EVs can lead to a diversity of EV-encapsulated cargo patterns. While this brings challenges to the research and application of EVs, it also provides opportunities for the application of EVs in disease diagnosis. Analyzing &#8220;fingerprints,&#8221; such as EV epigenetic cargo extracted from patient body fluids, is a potential strategy for rapid disease diagnosis. At the same time, because EVs can cross the blood-brain barrier and have low immunogenicity, they are often considered ideal carriers for delivering epigenetic drugs. Genetic manipulation can transform donor cells to produce engineered EVs loaded with specific cargo, which can then be delivered to recipient cells to reshape their epigenetic profiles and treat diseases.</span></p>
<p><span style="font-size: 15px;"><strong>Future Outlook</strong></span></p>
<p><span style="font-size: 15px;">EVs have gradually attracted attention as important mediators of intercellular communication, especially as emerging regulators of epigenetics. An increasing number of studies have demonstrated the mutual regulatory effects between EVs and the epigenome under both physiological and pathological conditions. In the future, comprehensive screening methods, including epigenomic analysis, are needed to explore the epigenetic factors involved in EV secretion or uptake. Delivering therapeutic cargo to reverse pathological epigenetic patterns in recipient cells may be a promising strategy. However, many challenges remain to be addressed. For example, the accuracy of engineered EV delivery and retention time <em>in vivo</em> need improvement. Delivering key enzymes related to epigenetic &#8220;writers,&#8221; &#8220;erasers,&#8221; and &#8220;readers&#8221; may be an ideal strategy, but potential side effects must be considered. The heterogeneity of EVs and the lack of specific markers also complicate the application of EV delivery for epigenetic drugs. As the field of EV biology rapidly develops, advanced technologies for single EV characterization, such as single EV imaging, flow cytometry, and multi-omics analysis, will help to deeply explore EV heterogeneity and significantly improve the accuracy and efficiency of EV drug delivery in future clinical applications.</span></p>
<p>&nbsp;</p>
<p><span style="font-size: 15px;"><strong>Reference:</strong></span></p>
<p><span style="font-size: 12px;">Haifeng Zhou et al. “Extracellular vesicles as modifiers of epigenomic profiles.” Trends in Genetics. Jun 5:S0168-9525(24)00109-4. doi: 10.1016/j.tig.2024.05.005</span></p>
<p><span style="font-size: 15px;"><strong>Related Services:</strong></span></p>
<p><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/exosome/therapeutic-application-of-exosome.htm">Therapeutic Application of Exosomes</a></span></p>
<p><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/exosome/diagnostic-application-of-exosomes.htm">Diagnostic Application of Exosomes</a></span></p>
<p><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/exosome/exosome-ngs-rna-next-gengeration-sequencing.htm">Exosome &#8211; NGS (RNA Next Gengeration Sequencing)</a></span></p>
]]></content:encoded>
					
		
		
			</item>
		<item>
		<title>Endocytosis Blocks Vesicular Secretion of Exosome Marker Proteins</title>
		<link>https://www.creative-biolabs.com/blog/exosome/exosome-review/endocytosis-blocks-vesicular-secretion-of-exosome-marker-proteins/</link>
		
		<dc:creator><![CDATA[biolabs]]></dc:creator>
		<pubDate>Tue, 28 May 2024 09:20:00 +0000</pubDate>
				<category><![CDATA[Exosome Review]]></category>
		<guid isPermaLink="false">https://www.creative-biolabs.com/blog/exosome/?p=321</guid>

					<description><![CDATA[Exosomes are secretory vesicles with a diameter of about 30 to 150 nanometers that play an important role in human health and disease. To better understand how cells release these vesicles, researchers<a class="moretag" href="https://www.creative-biolabs.com/blog/exosome/exosome-review/endocytosis-blocks-vesicular-secretion-of-exosome-marker-proteins/">Read More...</a>]]></description>
										<content:encoded><![CDATA[<p><span style="font-size: 15px;">Exosomes are secretory vesicles with a diameter of about 30 to 150 nanometers that play an important role in human health and disease. To better understand how cells release these vesicles, researchers from Johns Hopkins University studied the biogenesis of the most abundant human exosome marker proteins, the exosomal tetraspanins CD81, CD9, and CD63. The results showed that endocytosis inhibits the vesicular secretion of these proteins, and CD9 and CD81 disrupt endocytosis. In addition, the exosome biogenesis factor syntenin promotes the vesicular secretion of CD63 by preventing its endocytosis. Other endocytosis inhibitors also induce the plasma membrane accumulation and vesicular secretion of CD63. Finally, CD63 is an expression-dependent inhibitor of endocytosis that triggers the vesicular secretion of lysosomal proteins and the clathrin adaptor protein AP-2 mu2. These results indicate that the vesicular secretion of exosome marker proteins occurs mainly through a pathway independent of endocytosis. The relevant content was published online on May 10 in the internationally renowned comprehensive academic journal Science Advances under the title &#8220;Endocytosis blocks the vesicular secretion of exosome marker proteins&#8221;.</span></p>
<p><span style="font-size: 15px;"><img decoding="async" loading="lazy" class="aligncenter  wp-image-322" src="http://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/06/1.png" alt="" width="640" height="161" srcset="https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/06/1.png 1019w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/06/1-300x75.png 300w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/06/1-768x193.png 768w" sizes="(max-width: 640px) 100vw, 640px" /></span></p>
<p><span style="font-size: 15px;">Exosomes are small extracellular vesicles, approximately 30 to 150 nanometers in diameter, that share the same topology as cells and are enriched with specific exosomal marker proteins, especially exosomal tetraspanins. In mammals, exosomes are abundant in all biological fluids and can transmit signals and molecules between cells, playing a role in various physiological and disease processes. In addition, all cell types ubiquitously produce exosomes and other small extracellular vesicles, making them valuable as biosensors of tissue and organ health or disease. The biological normality of exosomes also makes them ideal nanovesicles for the delivery of vaccines, biologics, and other drugs. Therefore, understanding the biogenesis of exosome-sized secretory vesicles has become a major focus in the biomedical field.</span></p>
<p>&nbsp;</p>
<p><span style="font-size: 15px;">It is generally accepted that exosomal proteins bud from cells via a multistep, endocytosis-dependent pathway. This process involves the delivery of exosomal marker proteins to endosomes, loading these proteins into nascent intracellular lumenal vesicles (ILVs), and releasing the ILVs as exosomes when endosomes (also called multivesicular bodies) containing the ILVs fuse with the plasma membrane. This model has been extended to include CD63 and core proteins as recruitment factors for syntenin, syndecan-syntenin and CD63-syntenin complexes as recruitment factors for the protein Alix. Alix, in turn, recruits the ESCRT (endocytic structure-stimulating receptor) machinery to the endosomal membrane to drive ILV formation. This model is based on established protein interactions and is consistent with current understanding that ESCRTs promote outward vesicle budding (outward = away from the cytoplasm) and general membrane closure.</span></p>
<p>&nbsp;</p>
<p><span style="font-size: 15px;">Given that other organelle biogenesis pathways have been elucidated by studying their most abundant proteins, researchers have investigated exosome biogenesis by studying the most abundant exosomal proteins. In a recent side-by-side comparison of 24 human exosome marker proteins, researchers found that the exosomal tetraspanins CD81, CD9, and CD63 were more abundant in exosome-sized EVs than the other 21 marker proteins tested, such as syntenin, Alix, and the ESCRT protein TSG101. This result makes sense on several levels. First, CD81, CD9, and CD63 were the first proteins shown to be enriched in exosomes. Second, they have been used as exosome marker proteins for decades. However, initial studies on the trafficking and vesicle secretion of CD81, CD9, and CD63 did not support the current mainstream model of exosome biogenesis. Specifically, researchers found that CD81 and CD9 reside on the plasma membrane and bud from cells 15- and 5-fold more efficiently, respectively, than CD63, which is constantly endocytosed from the plasma membrane and resides in endosomes. Furthermore, attaching an endocytic signal to CD9 prevented CD9 from budding from cells, whereas mutating CD63&#8217;s endocytic signal induced its budding from cells. In short, these observations suggest that there is a large gap between current models of exosome biogenesis and the actual mechanisms by which cells bud exosome marker proteins.</span></p>
<p>&nbsp;</p>
<p><span style="font-size: 15px;">To further explore this gap, researchers investigated the effects of endocytic signals, endocytic inhibitors, and their expression levels on the vesicular secretion of CD81, CD9, and CD63. The results showed that endocytosis strongly inhibited the exosome secretion of all these highly abundant exosome marker proteins and triggered their destruction in the presence of CD81 and CD9. Moreover, six mechanistically different endocytic inhibitors were found to induce the vesicular secretion of CD63, which has an endocytic signal, but had no effect on the vesicular secretion of CD81, which lacks an endocytic signal. Additionally, high-level expression of CD63 was shown to directly bind the clathrin adaptor protein AP-2 subunit mu2, inhibit endocytosis, induce plasma membrane accumulation and vesicular secretion of lysosomal proteins, and trigger the vesicular secretion and cellular depletion of the AP-2 subunit mu2. These findings, along with other results, support the notion that exosome marker proteins are cleaved from cells to the plasma membrane and endosomal membranes primarily through a pathway independent of endocytosis.</span></p>
<p><span style="font-size: 15px;"><img decoding="async" loading="lazy" class="aligncenter  wp-image-323" src="http://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/06/2-scaled.jpg" alt="" width="653" height="347" srcset="https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/06/2-scaled.jpg 2560w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/06/2-300x159.jpg 300w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/06/2-1024x544.jpg 1024w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/06/2-768x408.jpg 768w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/06/2-1536x815.jpg 1536w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/06/2-2048x1087.jpg 2048w" sizes="(max-width: 653px) 100vw, 653px" /></span></p>
<p>&nbsp;</p>
<p>&nbsp;</p>
<p><span style="font-size: 15px;"><strong>Reference:</strong></span></p>
<p><span style="font-size: 12px;">Ai Y, Guo C, Garcia-Contreras M, et al. Endocytosis blocks the vesicular secretion of exosome marker proteins. Sci Adv. 2024;10(19):eadi9156. doi:10.1126/sciadv.adi9156</span></p>
<p><span style="font-size: 15px;"><strong>Related Services:</strong></span></p>
<p><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/exosome/exosomal-protein-isolation-and-profiling.htm">Exosomal Protein Isolation and Profiling Service</a></span></p>
<p><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/exosome/exosomal-surface-markers-based-exosome-characterization.htm">Exosomal Surface Markers-based Exosome Characterization</a></span></p>
<p><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/exosome/category-exosome-marker-cdna-plasmid-1118.htm">Exosome Marker cDNA Plasmid Products</a></span></p>
]]></content:encoded>
					
		
		
			</item>
		<item>
		<title>The Regulatory Role and Therapeutic Potential of Peripherally Derived Extracellular Vesicles in Neurodegenerative Diseases</title>
		<link>https://www.creative-biolabs.com/blog/exosome/exosome-review/the-regulatory-role-and-therapeutic-potential-of-peripherally-derived-extracellular-vesicles-in-neurodegenerative-diseases/</link>
		
		<dc:creator><![CDATA[biolabs]]></dc:creator>
		<pubDate>Sun, 28 Apr 2024 09:33:38 +0000</pubDate>
				<category><![CDATA[Exosome Review]]></category>
		<guid isPermaLink="false">https://www.creative-biolabs.com/blog/exosome/?p=307</guid>

					<description><![CDATA[Neurodegenerative diseases (NDDs), such as Alzheimer&#8217;s disease, Parkinson&#8217;s disease and amyotrophic lateral sclerosis, constitute a class of progressive diseases with complex pathogenesis. Traditional treatments face significant challenges due to drug delivery challenges.<a class="moretag" href="https://www.creative-biolabs.com/blog/exosome/exosome-review/the-regulatory-role-and-therapeutic-potential-of-peripherally-derived-extracellular-vesicles-in-neurodegenerative-diseases/">Read More...</a>]]></description>
										<content:encoded><![CDATA[<p><span style="font-size: 15px;">Neurodegenerative diseases (NDDs), such as Alzheimer&#8217;s disease, Parkinson&#8217;s disease and amyotrophic lateral sclerosis, constitute a class of progressive diseases with complex pathogenesis. Traditional treatments face significant challenges due to drug delivery challenges. The latest research has turned the focus to the peripheral system, especially extracellular vesicles (EVs), to explore their mechanism of traversing the blood-brain barrier and consequently their pivotal role in NDDs.</span></p>
<p>&nbsp;</p>
<p><span style="font-size: 15px;">Published on April 12, 2024, a review article titled &#8220;Peripheral extracellular vesicles in neurodegeneration: pathogenic influencers and therapeutic vehicles&#8221; appeared in the <em>Journal of Nanobiotechnology</em> (2024 Apr 12;22(1):170). This review details the latest scientific research progress in the regulation of brain NDDs by EVs from peripheral sources, including EVs from bone, adipose tissue and intestinal microorganisms. The article highlights the dual role of peripheral EVs in NDD progression: they can either promote pathological development, delay pathological progression, or serve as carriers of therapeutic agents. These studies provide inspiration and direction for the development of novel strategies for NDD prevention and control strategies.</span></p>
<p><img decoding="async" loading="lazy" class="aligncenter size-full wp-image-308" src="http://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/05/1.png" alt="" width="855" height="235" srcset="https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/05/1.png 855w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/05/1-300x82.png 300w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/05/1-768x211.png 768w" sizes="(max-width: 855px) 100vw, 855px" /></p>
<p><span style="font-size: 15px;"><strong>1. Research Progress</strong></span></p>
<p><span style="font-size: 15px;"><strong>EVs and NDDs derived from bone cells: </strong>In the complex communication network of the &#8220;bone-brain axis,&#8221; EVs derived from bone marrow mesenchymal stem cells, osteocytes, and immune cells within bones carry a variety of functional molecules such as proteins and miRNAs. These molecules regulate the survival, differentiation, and function of nerve cells, thereby maintaining the homeostasis of the nervous system. However, with the senescence of skeletal cells due to aging or the apoptosis induced by diseases, there is a notable decline in the abundance of neuroprotective molecules carried by bone-derived EVs. Consequently, the protective effects on the nervous system are compromised.</span></p>
<p><span style="font-size: 15px;"><strong>Adipose tissue-derived EVs and NDDs: </strong>Under healthy conditions, EVs secreted by adipose tissue are rich in a variety of beneficial adipokines, anti-inflammatory factors and growth factors. These factors work synergistically to promote neurogenesis, enhance synaptic plasticity, thereby improving cognitive function. However, in metabolic disorders such as obesity, adipose tissue produces EVs enriched within pro-inflammatory adipokines, deleterious miRNAs or metabolites. These aberrant molecules disrupt the normal function of the nervous system.</span></p>
<p><span style="font-size: 15px;"><strong>EVs and NDDs secreted by intestinal microorganisms:</strong> During aging or certain disease states, an imbalance in the intestinal flora occurs, characterized by a reduction in beneficial bacteria and an increase in harmful strains. EVs produced by beneficial bacteria such as Lactobacillus have neuroprotective effects and alleviate the pathological processes of neurodegenerative diseases by improving immune responses and reducing inflammatory responses. EVs released by harmful bacteria such as Pseudomonas aeruginosa are rich in harmful components, such as lipopolysaccharide, peptidoglycan and bacterial toxins. These EVs may cross the intestinal and blood-brain barriers and enter the central nervous system, thereby triggering immune responses and leading to the accumulation of neuroinflammation and neurotoxic proteins, and exacerbating neurodegeneration.</span></p>
<p><span style="font-size: 15px;"><strong>Peripheral-derived EVs as potential therapeutic vehicles for NDDs:</strong> Given that peripheral EVs are able to cross the blood-brain barrier and play a key role in NDD development. By regulating the production, release and transportation of peripheral EVs, and optimizing the types and contents of therapeutic molecules they carry, it is expected to achieve effective interventions in NDDs. In addition, using gene editing technologies to enhance the neuroprotective capabilities or reduce the neuropathogenic potential of peripheral EVs holds promise for unveiling new strategies for the prevention and treatment of NDDs.</span></p>
<p>&nbsp;</p>
<p><span style="font-size: 15px;"><strong>2. Future Prospects</strong></span></p>
<p><span style="font-size: 15px;">Although EVs have powerful functions, their biogenetic properties and secretion mechanisms have yet to be thoroughly understood, and their clinical application still faces many challenges. To promote the transition of EVs from laboratory research to clinical application, it is necessary to select cells that produce EVs, optimize EVs preparation protocols, and establish standards. In the future, the integration of nanotechnology, bioengineering, and molecular biology will be beneficial in establishing targeted delivery therapies based on EVs. At the same time, the continuous advancement of omics technology and systems biology is expected to reveal the molecular characteristics of peripheral EVs and provide a deeper understanding and support for their application in the treatment of NDDs.</span></p>
<p><span style="font-size: 15px;">This review not only reveals the complex regulatory role of peripherally derived EVs in NDDs but also inspires the development of new therapeutic strategies. Further research in the future will assist in the treatment of NDDs by regulating the function of peripheral EVs or designing efficient drug delivery systems based on EVs.</span></p>
<p><img decoding="async" loading="lazy" class="aligncenter  wp-image-309" src="http://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/05/2.png" alt="" width="704" height="491" srcset="https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/05/2.png 1350w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/05/2-300x209.png 300w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/05/2-1024x714.png 1024w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/05/2-768x535.png 768w" sizes="(max-width: 704px) 100vw, 704px" /></p>
<p><span style="font-size: 15px;"><strong>Reference</strong><strong>:</strong></span></p>
<p><span style="font-size: 12px;">Liu X, Shen L, Wan M, Xie H, Wang Z. Peripheral extracellular vesicles in neurodegeneration: pathogenic influencers and therapeutic vehicles. J Nanobiotechnology. 2024;22(1):170. Published 2024 Apr 12. doi:10.1186/s12951-024-02428-1</span></p>
<p>&nbsp;</p>
<p><span style="font-size: 15px;"><strong>Related Services:</strong></span></p>
<p><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/exosome/neurological-diseases-diagnosis-applied-exosomes.htm">Neurological Diseases Diagnosis-Applied Exosomes</a></span></p>
<p><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/exosome/bone-tissue-exosome.htm">Bone Tissue Exosome Research and Application</a></span></p>
<p><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/exosome/adipose-tissue-exosome.htm">Adipose Tissue Exosome Research and Application</a></span></p>
]]></content:encoded>
					
		
		
			</item>
		<item>
		<title>Extracellular Vesicles as Biomarkers for Detection and Therapeutic Applications</title>
		<link>https://www.creative-biolabs.com/blog/exosome/exosome-therapy/extracellular-vesicles-as-biomarkers-for-detection-and-therapeutic-applications/</link>
		
		<dc:creator><![CDATA[biolabs]]></dc:creator>
		<pubDate>Thu, 28 Mar 2024 09:04:13 +0000</pubDate>
				<category><![CDATA[Exosome Review]]></category>
		<category><![CDATA[Exosome Therapy]]></category>
		<guid isPermaLink="false">https://www.creative-biolabs.com/blog/exosome/?p=293</guid>

					<description><![CDATA[Extracellular vesicles (EVs) secreted by all cell types are involved in the intercellular communication, delivering regulatory factors that influence cell and tissue phenotypes in both normal and diseased tissues. Therefore, EVs represent<a class="moretag" href="https://www.creative-biolabs.com/blog/exosome/exosome-therapy/extracellular-vesicles-as-biomarkers-for-detection-and-therapeutic-applications/">Read More...</a>]]></description>
										<content:encoded><![CDATA[<p><span style="font-size: 15px;">Extracellular vesicles (EVs) secreted by all cell types are involved in the intercellular communication, delivering regulatory factors that influence cell and tissue phenotypes in both normal and diseased tissues. Therefore, EVs represent a promising source of biomarker targets for disease diagnosis in blood and samples. However, the sensitive detection of biomarkers from EVs originating from specific cell populations remains a significant challenge in the analysis of complex biological samples. Researchers from Tulane University School of Medicine have compiled current innovative methods to simplify the isolation of EVs and discuss how to improve the sensitivity of EV detection procedures needed for clinical applications in EV-based genetic diagnosis and therapy. These methods encompass cutting-edge technologies such as nanotechnology and microfluidic techniques, facilitating the characterization of EVs. Furthermore, the study outlines both the opportunities and challenges in translating of EV genetic testing into clinical practice. This relevant study was published online on March 12 in ACS Nano, a prestigious academic journal renowned for its contributions to the field of nanomaterials, under the title &#8220;A Panorama of Extracellular Vesicle Applications: From Biomarker Detection to Therapeutics&#8221;.</span></p>
<p><img decoding="async" loading="lazy" class="aligncenter wp-image-295" src="http://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/04/1.jpg" alt="" width="687" height="497" srcset="https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/04/1.jpg 772w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/04/1-300x217.jpg 300w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/04/1-768x555.jpg 768w" sizes="(max-width: 687px) 100vw, 687px" /></p>
<p><span style="font-size: 15px;">Extracellular vesicles (EVs) play an important role in intercellular communication and regulation, influencing processes related to disease pathology. Given their widespread secretion by various cell types, EVs are implicated in both local and systemic cytopathological responses. Rapid, accurate, and sensitive detection methods are developed by targeting EV-specific biomarkers to detect specific EV populations associated with disease processes. EVs, abundant in most body fluids, simplify diagnostic sample collection, carrying a plethora of biomolecules such as proteins, mRNA, miRNA, lncRNA, DNA, lipids, and metabolites. These biomarkers, derived from EVs secreted by damaged or diseased cells, harbor rich diagnostic and prognostic information, governing intercellular communication, maintenance, cell maturation, and immune responses related to disease development and pathology. Therefore, EV-derived biomarkers are proposed candidates for infectious, chronic, and malignant diseases.</span></p>
<p><span style="font-size: 15px;">However, sensitive and accurate detection of specific EV biomarkers is complicated by the presence of diverse EV populations and nanoparticle contaminants (protein aggregates, lipoproteins, cell debris, etc.) in biological samples. Single EV analysis methods aim to circumvent this issue, enabling evaluation of the complete spectrum of EVs and their potential roles in disease pathology. However, this approach is still nascent due to incomplete understanding of EV biogenesis, technical limitations, and a lack of standardization and validation methods. Extensive research is directed towards developing EV-based therapeutics capitalizing on their desirable properties, including stability, tissue permeability, cell tissue selectivity, and drug loading capacity, to modulate disease development and progression. This involves modifying the content or surface molecules of specific EV populations through genetic engineering, transfection/fusion, or chemical modification to alter their regulatory functions or cellular targeting specificity. However, challenges persist in clinical EV diagnostic applications, encompassing difficulties in sample collection, purification, quantification, processing, isolating EVs for specific cell types, and understanding their pathological effects. Guidelines such as the &#8220;Minimum Information for Research on Extracellular Vesicles&#8221; (MISEV) offer recommended procedures for EV characterization, processing, and analysis, streamlining the development of clinically-ready EV therapeutics. Similarly, method-specific guidance aids in driving the development of diagnostic tools using standardized techniques like quantitative real-time polymerase chain reaction (qPCR) and flow cytometry, and other specialized methods that require standardized guidance to produce reliable data. Leveraging automated systems for EV isolation and characterization also accelerates the development of clinically feasible EV-based diagnostic applications.</span></p>
<p><span style="font-size: 15px;">Further development of standardized EV handling procedures is still necessary to ensure the preservation of biomarker integrity before analysis, especially in early diagnostic samples where the signal intensity might be very low due to the assessment of low concentrations of EVs associated with disease development or progression. This is especially true in longitudinal samples of biomarkers. Additionally, standardized EV preparation and characterization methods are imperative to ensure the consistent safety and efficacy of EV treatments. Moreover, additional studies are warranted to pinpoint EV biomarkers associated with effective treatment response, although “omics” studies can provide important insights into this issue. Clinical applications using EVs for diagnosis or therapy demand rational approaches that simplify workflows and improve the performance of current methods. Consequently, researchers undertook a comprehensive review of this field, describing the advancements and persistent challenges encountered in EV-based diagnosis and treatment. In this review, researchers mainly discussed in detail the following aspects:</span></p>
<p><strong><span style="font-size: 15px;">1. Advancements in EV Detection Technology</span></strong></p>
<p><span style="font-size: 15px;">Traditional EV analysis methods, including polymerase chain reaction (PCR), Western blotting (WB) and enzyme-linked immunosorbent assay (ELISA), are known for their time-consuming and labor-intensive, have moderate sensitivity, and requirement for separate EV purification steps, thereby limiting their ability for clinical applications. However, tremendous progress has been made in recent years to improve EV analysis methods, aiming to augment their sensitivity, specificity and utility in clinical settings. Customized nanomaterials and microfluidic platforms are currently under investigation to further enhance their performance characteristics . EV detection methods such as fluorescence, surface plasmon resonance (SPR), surface-enhanced Raman spectroscopy (SERS), electrochemistry and aptamers can all be combined to achieve optimal performance on the EV detection platform, facilitating sensitive signal recognition.</span></p>
<p><strong><span style="font-size: 15px;">2. Single EV Analysis Technology and Its Diagnostic Potential</span></strong></p>
<p><span style="font-size: 15px;">In recent years, there has been a concentrated effort in translational EV research towards the development of advanced methods capable of biophysical characterization at the single EV level. EVs present in biological samples exhibit significant heterogeneity, encompassing phenotypes that mirror diverse cell types across various tissues. For example, plasma EVs may originate from cells representing different lineages or fate states within a tissue, or even cells with distinct genetic backgrounds within a tumor. Techniques focusing on individual EV profiling can elucidate aspects of this heterogeneity among EV subpopulations, such as size and composition. They are adept at detecting low concentrations of EV biomarkers in complex samples and establishing associations with specific EV biomarkers on individual EVs or EV subpopulations. Such analyses furnish invaluable insights into disease development and progression or treatment response, thus enriching the diagnostic potential of EV analysis in complex samples. Single EV analysis methods encompass a diverse array of techniques, several of which do not require the use of exogenous labels. These include nanoparticle tracking analysis (NTA), cryo-electron microscopy (cryo-EM), atomic force microscopy (AFM), and laser tweezer Raman spectroscopy. However, many of these techniques offer limited label-free information or may falter in detection without independent EV isolation procedures. For instance, label-free methods like NTA only provide an estimation of the EV diameter distribution within the population. While cryo-electron microscopy and atomic force microscopy can provide some insights into the conformational phenotypic distribution, all three methods might struggle to distinguish EVs from other entities like protein aggregates and viruses that could contaminate EV isolates. Consequently, an increasing number of individual EV analysis methods are incorporating fluorescent affinity tags to identify specific EV subpopulations for analysis.</span></p>
<p><strong><span style="font-size: 15px;">3. Diagnosis, Prognosis, and Therapeutic Applications of EVs</span></strong></p>
<p><span style="font-size: 15px;">EVs have great potential in diagnostic applications across infectious, chronic and malignant diseases due to their ability to discern and differentiate specific diseases as well as discrete disease stages. Additionally, they reflect cellular responses to therapeutic interventions through changes in disease-associated EV biomarkers. Enhanced EV isolation and characterization methodologies are poised to refine EV diagnostics and therapeutics in development, thereby augmenting their prospects for clinical translation. Notably, machine learning methods show promise in discerning and characterizing specific EV populations.</span></p>
<p><img decoding="async" loading="lazy" class="aligncenter wp-image-294" src="http://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/04/2.jpg" alt="" width="742" height="442" srcset="https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/04/2.jpg 1871w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/04/2-300x179.jpg 300w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/04/2-1024x611.jpg 1024w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/04/2-768x458.jpg 768w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/04/2-1536x916.jpg 1536w" sizes="(max-width: 742px) 100vw, 742px" /></p>
<p>&nbsp;</p>
<p><span style="font-size: 15px;"><strong>Reference</strong><strong>:</strong></span></p>
<p><span style="font-size: 15px;">Das S, Lyon CJ, Hu T. A Panorama of Extracellular Vesicle Applications: From Biomarker Detection to Therapeutics. ACS Nano. 2024 Mar 12. doi: 10.1021/acsnano.4c00666. Epub ahead of print. PMID: 38471757.</span></p>
<p><span style="font-size: 15px;"><strong>Related Services:</strong></span></p>
<p><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/exosome/single-cell-exosome-combined-research-services.htm">Single-Cell &amp; Exosome Combined Research Services</a></span></p>
<p><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/exosome/exosomal-surface-markers-based-exosome-characterization.htm">Exosomal Surface Markers-based Exosome Characterization</a></span></p>
]]></content:encoded>
					
		
		
			</item>
		<item>
		<title>Extracellular Vesicles Incorporate Retrovirus-Like Capsids for Enhanced Packaging and Systemic Delivery of mRNA to Neurons</title>
		<link>https://www.creative-biolabs.com/blog/exosome/exosome-tech/extracellular-vesicles-incorporate-retrovirus-like-capsids-for-enhanced-packaging-and-systemic-delivery-of-mrna-to-neurons/</link>
		
		<dc:creator><![CDATA[biolabs]]></dc:creator>
		<pubDate>Thu, 29 Feb 2024 09:26:50 +0000</pubDate>
				<category><![CDATA[Exosome Tech]]></category>
		<guid isPermaLink="false">https://www.creative-biolabs.com/blog/exosome/?p=278</guid>

					<description><![CDATA[The blood-brain barrier (BBB) poses a significant challenge to the systemic delivery of mRNA to diseased neurons.While extracellular vesicles (EVs) derived from leukocytes can traverse the BBB, efficiently loading lengthy mRNAs into<a class="moretag" href="https://www.creative-biolabs.com/blog/exosome/exosome-tech/extracellular-vesicles-incorporate-retrovirus-like-capsids-for-enhanced-packaging-and-systemic-delivery-of-mrna-to-neurons/">Read More...</a>]]></description>
										<content:encoded><![CDATA[<p><span style="font-size: 15px;">The blood-brain barrier (BBB) poses a significant challenge to the systemic delivery of mRNA to diseased neurons.While extracellular vesicles (EVs) derived from leukocytes can traverse the BBB, efficiently loading lengthy mRNAs into EVs and improving their uptake by neurons remains problematic. A recent collaboration between Cornell University and the Massachusetts Institute of Technology (MIT) has addressed this issue, as outlined in an article published in the journal Nature Biomedical Engineering. Their approach involves a method to enhance mRNA loading and neuronal uptake by engineering leukocytes to produce EVs containing retrovirus-like mRNA packaging shells.</span></p>
<p><span style="font-size: 15px;"><img decoding="async" loading="lazy" class="aligncenter wp-image-247" src="http://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/03/1.jpg" alt="" width="611" height="409" srcset="https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/03/1.jpg 764w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/03/1-300x201.jpg 300w" sizes="(max-width: 611px) 100vw, 611px" /></span></p>
<p><span style="font-size: 15px;">Systemic drug delivery to neurons is limited by the BBB, as well as by low uptake rates of vectors and inefficient release onto neurons. Most biologics, including recombinant proteins, therapeutic antibodies, and nucleic acids, are unable to penetrate the BBB. Adeno-associated viruses (AAVs) can deliver DNA to neurons, while recombinant proteins and therapeutic antibodies can cross the BBB via receptor-mediated transporters specific to certain peptides, such as insulin or transferrin. Messenger RNA (mRNA) has emerged as a promising therapeutic agent for preventing and treating diseases. However, for mRNA to be effective in the body, it requires a safe, efficient, and stable delivery system that shields it from degradation and facilitates cellular uptake and release. Various viral and nonviral vectors have been developed for this purpose, including retroviral vectors, lipid nanoparticles, polymers, protein derivatives, and membrane-enclosed vesicles. However, achieving efficient and targeted delivery of RNA therapeutics <em>in vivo</em> remains a formidable challenge.</span></p>
<p><span style="font-size: 15px;">Inflammatory stimulation of the brain leads to the destruction of the BBB. Brain microvascular endothelial cells (BMECs) exhibit increased permeability, accompanied by an upregulation of leukocyte adhesion molecules. This facilitates the entry of circulating leukocyte-derived extracellular vesicles (EVs) into the brain, rendering them excellent candidates for neuron-targeted drug delivery. The permeability of the BBB to leukocyte EVs is heightened in various neurological diseases, including age-related chronic inflammation, neurodegenerative diseases, and more severe pathological conditions such as systemic inflammation and secondary injuries (e.g., stroke). However, the clinical translation of EV-based therapeutics for these diseases is limited by low payload encapsulation efficiency and the inability to control the molecules loaded into EVs from donor cells. The payload of EVs may comprise proteins, DNA, RNA, lipids, nutrients, and metabolic waste products. The exclusion of unnecessary cellular components from EVs is challenging, impacting both loading capacity and the potential delivery of harmful components to the target.</span></p>
<p>&nbsp;</p>
<p><span style="font-size: 15px;">Various systems have been developed for loading small RNAs (such as siRNA and miRNA) into EVs, but efficiently enriching of long mRNAs into EVs remains a challenge. Extremely low copy numbers of endogenous EV-associated RNAs have been reported, ranging from 0.02 to 1 RNA per EV. Small RNAs are more efficiently packaged into EVs compared to long mRNAs (0.01 to 1 miRNA vs. 0.001 intact long RNAs per EV). Only 8% of donor cells exhibited detectable mRNA in their EVs. Previous methods for loading mRNA into EVs include passive and active encapsulation. For example, by incubating with macrophage-derived EVs following ultrasound and extrusion, or treating with saponins to address Parkinson&#8217;s disease. However, this post-EV isolation and loading approach has limited capacity as EVs already filled with donor cell components cannot be unloaded to accommodate drugs. Alternatively, EVs can be engineered at the mother cell level. The efficient and selective incorporation of mRNA into EVs under natural conditions is crucial for designing EVs as therapeutic drug carriers.</span></p>
<p><span style="font-size: 15px;">To enhance the loading of RNA payloads into EVs, the authors introduced retrovirus-like protein shells into the EV lumen. These protein shells naturally occur in the human brain and play a role in facilitating intercellular communication within the central nervous system. They originate from transposable genomic elements spanning eukaryotic domains, known as long terminal repeat (LTR) retrotransposons, which share an evolutionary origin with retroviruses. LTR retroviruses, along with the retrotransposon coat protein (Gag) homolog Arc (activity-regulated cytoskeleton-associated protein), may have evolved in parallel and function similarly to infectious RNA retroviruses. Another Gag homolog, PEG10, was recently modified to form virus-like particles for in vitro mRNA delivery. The Arc protein self-assembles into a virus-like shell to encapsulate mRNA, which is then released from neurons and delivered to receiving neurons via receptor-mediated endocytosis. Although Arc EVs hold potential as drug delivery vectors, their use in drug delivery remains incompletely studied. Arc and Gag are reported to be inefficient at mRNA transduction and less specific for payloads without the addition of their untranslated regions (UTRs). In this study, an Arc 5’ UTR (A5U) was included in the payload build to stabilize the shell and increase payload carrying capacity. Therefore, the authors introduced the Arc protein coat into EVs and added the A5U RNA motif stabilizer to achieve effective mRNA encapsulation and delivery.</span></p>
<p><span style="font-size: 15px;">In addition to enhanced payload-carrying capabilities, the system offers several other advantages. First, engineered retrotransposon Arc extracellular vesicles (eraEVS) produced by autologous leukocytes are immunologically inert and accumulate in the inflammatory microenvironment, crossing the blood-brain barrier with the assistance of membrane molecules from donor leukocytes. Furthermore, the Arc component recruits wrapping proteins during self-assembly, promoting the cellular uptake of EVs through its natural function in mediating molecular exchange between neurons. Moreover, the virus-like shell renders eraEVs more stable than other engineered RNA-loaded EVs, protecting the payload from nuclease degradation until its release is triggered. Besides leveraging these unique virus-like properties, eraEVs are safe, serving as short-lived drug carriers incapable of replication, infection, or genetic information insertion into the recipient&#8217;s genome. Crucially, relying on the natural targeting capabilities of EVs across different cell types, eraEVs can be generated from various donor cells and applied in diverse biomedical contexts. This study highlights an endogenous virus-like system capable of loading and delivering mRNA <em>in vivo</em>, specifically targeting diseased neurons through systemic administration.</span></p>
<p style="text-align: center;"><span style="font-size: 15px;"><img decoding="async" loading="lazy" class="aligncenter wp-image-248" src="http://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/03/2.jpg" alt="" width="629" height="690" srcset="https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/03/2.jpg 1277w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/03/2-273x300.jpg 273w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/03/2-933x1024.jpg 933w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/03/2-768x843.jpg 768w" sizes="(max-width: 629px) 100vw, 629px" /><span style="font-size: 12px;">Enhanced stability of Arc EV via A5U motif</span></span></p>
<p>&nbsp;</p>
<p><span style="font-size: 15px;">The study transfected immortalized and primary bone marrow-derived leukocytes with DNA or RNA encoding the activity-regulated cytoskeleton-associated protein (Arc) of coat formation and the RNA element of the Arc 5&#8242; untranslated region that stabilizes the coat. These engineered EVs inherit the endothelial adhesion molecules of donor leukocytes, recruit endogenous packaging proteins to their surface, cross the BBB, and enter sites of neuroinflammation in neurons. These EVs generated from autologous donor leukocytes are immunologically inert and enhance neuronal uptake of packaged mRNA in a mouse model of low-grade chronic neuroinflammation.</span></p>
<p>&nbsp;</p>
<p>&nbsp;</p>
<p><span style="font-size: 15px;"><strong>Reference</strong><strong>:</strong></span></p>
<p><span style="font-size: 12px;">Gu W, Luozhong S, Cai S, et al. Extracellular vesicles incorporating retrovirus-like capsids for the enhanced packaging and systemic delivery of mRNA into neurons. Nat Biomed Eng. Published online February 19, 2024. doi:10.1038/s41551-023-01150-x</span></p>
<p>&nbsp;</p>
<p><span style="font-size: 15px;"><strong>Related Services:</strong></span></p>
<p><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/exosome/brain-targeted-exosome-modification-service.htm">Brain-Targeted Exosome Modification Service</a></span></p>
<p><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/exosome/central-nervous-system-cns-disorder.htm">Exosome in CNS Disorder</a></span></p>
<p>&nbsp;</p>
]]></content:encoded>
					
		
		
			</item>
		<item>
		<title>Self-Stimulating Release Hydrogel Enhances the Therapeutic Effect of MSC-EVs on Alzheimer&#8217;s Disease</title>
		<link>https://www.creative-biolabs.com/blog/exosome/exosome-therapy/self-stimulating-release-hydrogel-enhances-the-therapeutic-effect-of-msc-evs-on-alzheimers-disease/</link>
		
		<dc:creator><![CDATA[biolabs]]></dc:creator>
		<pubDate>Sun, 28 Jan 2024 09:41:55 +0000</pubDate>
				<category><![CDATA[Exosome Therapy]]></category>
		<guid isPermaLink="false">https://www.creative-biolabs.com/blog/exosome/?p=227</guid>

					<description><![CDATA[Extracellular vesicle (EV)-based therapeutic approaches still pose challenges in clinical application due to their rapid clearance, limited residence, and low yield. Although hydrogels possess the ability to impede physiological clearance and increase<a class="moretag" href="https://www.creative-biolabs.com/blog/exosome/exosome-therapy/self-stimulating-release-hydrogel-enhances-the-therapeutic-effect-of-msc-evs-on-alzheimers-disease/">Read More...</a>]]></description>
										<content:encoded><![CDATA[<p><span style="font-size: 15px;">Extracellular vesicle (EV)-based therapeutic approaches still pose challenges in clinical application due to their rapid clearance, limited residence, and low yield. Although hydrogels possess the ability to impede physiological clearance and increase regional retention, they often fail to efficiently release the bound EVs, resulting in reduced accessibility and bioavailability. Recently, scientists published an article in <em>Adv Mater</em> reporting on an intelligent hydrogel where the release of EVs is regulated by proteins on the EV membrane. By utilizing EV membrane enzymes to promote hydrogel degradation, sustained retention and self-stimulated EV release can be achieved at the administration site. To accomplish this goal, membrane proteins with matrix-degrading activity in extracellular vesicles derived from mesenchymal stem cells (MSC-EVs) were identified using comparative proteomics. Subsequently, a hydrogel composed of self-assembling peptides that was quickly degraded by membrane enzymes present in MSC-EVs was designed and synthesized. After intranasal administration, this peptide hydrogel can promote sustained and thermosensitive release of MSC-EVs, thereby prolonging the retention time of MSC-EVs and significantly enhancing their potential to treat Alzheimer&#8217;s disease.</span></p>
<p><img decoding="async" loading="lazy" class="aligncenter  wp-image-220" src="http://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/02/1.jpg" alt="" width="621" height="292" srcset="https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/02/1.jpg 862w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/02/1-300x141.jpg 300w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/02/1-768x362.jpg 768w" sizes="(max-width: 621px) 100vw, 621px" /></p>
<p><span style="font-size: 15px;">Extracellular vesicles (EVs) are cell-derived structures that carry biologically active molecules, including proteins, mRNA, and miRNA. These molecules can target specific receptor cells and initiate signaling pathways that regulate various biological functions. In addition, EVs can transport large molecules between cells. Due to these properties, EVs offer unique opportunities for the development of new therapies. Notably, mesenchymal stem cell-derived EVs (MSC-EVs) are considered promising alternatives to stem cell transplantation therapy. MSC-EVs can stimulate angiogenesis, inhibit inflammation, resist apoptosis, and promote regeneration. This makes MSC-EVs potential candidates for the management of neurodegenerative diseases. The author&#8217;s research team recently completed the first clinical trial (NCT04388982) in patients with Alzheimer&#8217;s disease (AD), in which human adipose MSC-EVs were administered intranasally twice weekly for 12 weeks, followed by continuous monitoring to evaluate the safety and efficacy of MSC-EVs for AD treatment. Encouragingly, no adverse events were reported during visits in all groups. Additionally, Alzheimer&#8217;s Disease Assessment Scale (ADAS-cog) scores decreased by 2.33 ± 1.19 at week 12 compared to baseline, and Montreal Cognitive Assessment baseline scores increased by 2.38 ± 0.58, indicating improvements in cognitive function. Notably, the ADAS-cog score in the mid-dose group continued to decline until week 36 when it dropped by 3.98 points. This clinical trial highlights the potential of MSC-EVs in treating central neurodegenerative diseases. However, clinical translation of EV-based therapies still faces challenges such as low EV retention at the administration site and rapid systemic clearance. At the same time, limited production output and high costs also hinder the accessibility of EVs. Therefore, the key to future therapeutic applications must lie in the development of controllable, sustained delivery systems to prolong the retention time of EVs in the body and enhance their bioavailability.</span></p>
<p><span style="font-size: 15px;">Hydrogels have tunable delivery properties that can be precisely controlled by adjusting parameters such as material composition, degree of cross-linking and pore structure. This tunability enables hydrogels to achieve diverse release kinetics, from fast to slow release, directly affecting the efficacy and potential side effects of therapeutic agents. To improve the clinical translation potential of EVs, studies have designed hydrogel-based formulations. These formulations contain hydrophilic polymers that form cross-linked networks in aqueous solutions. However, conventional hydrogels typically release encapsulated drugs through the inherent but gradual disintegration of the hydrogel and diffusion of the drug. They lack the ability to modulate drug release, thus leading to reduced efficacy of EVs. To address the challenges faced by EVs delivery, there is an urgent need to develop a hydrogel system with controlled release properties, especially designed for EVs delivery.</span></p>
<p><span style="font-size: 15px;">Extracellular vesicles (EVs) are widely recognized as key mediators of local and long-distance intercellular communication. To achieve effective long-distance intercellular communication, EVs must exhibit excellent tissue/cell penetration capabilities, especially in the complex extracellular matrix (ECM). Permeability is largely facilitated by those EV membrane proteins with ECM-degrading activity. To overcome the challenges of EV release in hydrogels and enhance their functionality, the authors proposed the development of a smart hydrogel that can release EVs based on the enzymatic activity of EV membrane proteins. This hydrogel is expected to prolong the retention time of EVs at the administration site and achieve their controlled release. The self-stimulated release process not only enhances stability but also delays clearance and achieves a more reliable sustained effect, thereby improving EV bioavailability. These properties are crucial to expand application scenarios and enhance the clinical translation potential of EVs.</span></p>
<p><span style="font-size: 15px;">To test the above hypothesis, the author&#8217;s team used human adipose MSC-EVs as a model to construct a hydrogel responsive to MSC-EVs&#8217; membrane proteins. They investigated the effect of hydrogels on the efficacy of MSC-EVs in treating Alzheimer’s disease (AD), which is the most common neurodegenerative disease and a major cause of dementia. To evaluate the potential of MSC-EVs&#8217; membrane proteins as triggers for enzyme-catalyzed hydrogel degradation, the permeability of MSC-EVs was first verified. Compared to EVs derived from the microglial cell line BV2, MSC-EVs exhibited higher permeability. Subsequently, comparative proteomic analysis was conducted, identifying specific membrane proteins on MSC-EVs that exhibited matrix-degrading activity. Based on the enzymatic activity of MSC-EVs membrane proteins, the authors designed and synthesized a hydrogel composed of self-assembling peptides that is easily degraded by membrane enzymes present in MSC-EVs. After intranasal administration, this smart release hydrogel extended the retention time of MSC-EVs at the administration site, released MSC-EVs in a controlled manner, and significantly enhanced the efficacy and clinical translational potential of MSC-EVs for AD treatment. This study proposes a smart hydrogel design method based on comparative proteomics that can significantly improve the applicability of EVs in clinical settings.</span></p>
<p><img decoding="async" loading="lazy" class=" wp-image-221 aligncenter" src="http://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/02/2.jpg" alt="" width="631" height="507" srcset="https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/02/2.jpg 1367w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/02/2-300x241.jpg 300w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/02/2-1024x822.jpg 1024w, https://www.creative-biolabs.com/blog/exosome/wp-content/uploads/sites/7/2024/02/2-768x617.jpg 768w" sizes="(max-width: 631px) 100vw, 631px" /></p>
<p style="text-align: center;"><span style="font-size: 12px;">MSC-EVs-GEL more effectively alleviate neuronal damage and promote neurogenesis in 5×FAD AD model mice.</span></p>
<p>&nbsp;</p>
<p><span style="font-size: 15px;"><strong>Reference</strong><strong>:</strong></span></p>
<p><span style="font-size: 15px;">Huang M, Zheng M, Song Q, et al. Comparative Proteomics Inspired Self-Stimulated Release Hydrogel Reinforces the Therapeutic Effects of MSC-EVs on Alzheimer&#8217;s Disease. Adv Mater. Published online December 29, 2023. doi:10.1002/adma.202311420</span></p>
<p>&nbsp;</p>
<p><span style="font-size: 15px;"><strong>Related Services:</strong></span></p>
<p><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/exosome/therapeutic-exosomes-for-parkinsons-disease.htm">Therapeutic Exosomes for Parkinson&#8217;s Disease</a></span></p>
<p><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/exosome/central-nervous-system-cns-disorder.htm">Exosome in CNS Disorder</a></span></p>
]]></content:encoded>
					
		
		
			</item>
	</channel>
</rss>