![]() ![]() 11–13 Furthermore, the biological function of EVs is primarily modulated by its molecular makeup, surface markers, and compositions, which determine the pharmacological and pharmacokinetic behavior of EVs in vivo. Similar to most of the commonly used therapeutic nanoparticles, the major challenge in employing the EVs-based drug delivery system is the limited bioavailability due to its short half-life (less than 10 minutes) and fast hepatic clearance following systemic intravenous administration. With the recent advancement of biomaterial-based nanotechnologies, an increasing number of customized EVs derivatives have been entering clinical trials to evaluate their efficacies for the targeted delivery of therapeutic drugs to minimize systemic toxicity in patients. 1–5 In addition to its amenability to scalable production in the current good manufacturing practice (GMP) system, human cell-derived EVs possess minimal immunogenicity and toxicity, 6–9 which make them an ideal drug delivery system in critical clinical applications. Among different types of EVs, the smallest type or microvesicles (MVs) are widely employed as naturally derived therapeutic vehicles with great versatility in terms of cargo types, eg, peptide, membrane protein, miRNA, and mRNA, as well as specificity of delivery location. Keywords: exosome, glycosylation, glycan, drug deliveryĮxtracellular vesicles (EVs) are cell-secreted nanosized particles containing a variety of biomaterials in a lipid bilayer encapsulated form. Systemic administration of the EVs with the equivalent dose of 1.5μg/kg of exosomal IL12 achieved satisfactory tumor growth inhibition and good tolerability.Ĭonclusion: The combinatorial approach of EVs surface engineering conferred HEK293-EVs with reduced non-specific clearance and enhanced tumor targeting efficacy, which constituted an efficient delivery platform for critical cancer therapeutics like IL12. The ITGB1 −mscIL12 +HN3 +Deg EVs activated mouse splenocytes with high potency. Loading of HN3 conferred the ITGB1 −Deg EVs with tumor-specific tropism for both subcutaneous and metastasized tumors in mice. ITGB1 removal did not significantly alter the pharmacokinetic behaviors of HEK293-EVs, whereas the ITGB1 −Deg EVs exhibited enhanced systemic exposure with reduced hepatic accumulation. Deglycosylation of ITGB1 − EVs gave rise to inhibition of the EVs uptake by activated RAW264.7 cells. Results: Removal of ITGB1 led to the broad suppression of integrins on the EVs surface, resulting in a decrease in cellular uptake. ITGB1 −Deg EVs were further loaded with glypican-3 (GPC3)-specific nanobody (HN3) and mouse single-chain IL12 (mscIL12) to generate ITGB1 −mscIL12 +HN3 +Deg EVs, for evaluation of tumor tropism and therapeutic potential in a mice model of hepatocellular carcinoma. ![]() Methods: The major cell adhesion molecule on the HEK293-derived EVs, integrin β 1 (ITGB1), was knocked out (KO) by CRISPR/Cas9-mediated gene editing, followed by deglycosylation to generate ITGB1 −Deg EVs for the subsequent pharmacokinetic and biodistribution analyses. As a proof-of-concept, we investigated the therapeutic potentials of a multi-modal EVs system carrying a tumor-specific nanobody and the immuno-stimulant interleukin-12 (IL12) using in vivo models of hepatocellular carcinoma. We aimed to explore a series of surface engineering approaches to: 1) reduce the non-specific adhesion of EVs, and 2) improve their enrichment in the target tissue. Naïve EVs face numerous issues that limit their applications, such as fast clearance, hepatic accumulations, and a lack of target-specific tropism. ![]() Jing Zhang, 1 Haijing Song, 2 Yanan Dong, 1 Ganghui Li, 3 Jun Li, 1 Qizhe Cai, 4 Shoujun Yuan, 5 Yi Wang, 1 Haifeng Song 1ġState Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, People’s Republic of China 2Emergency Medicine, PLA Strategic Support Force Medical Center, Beijing, 100101, People’s Republic of China 3China Pharmaceutical University, Nanjing, 211198, People’s Republic of China 4Department of Echocardiography, Beijing Chao Yang Hospital, Capital Medical University, Beijing, 100020, People’s Republic of China 5Beijing Institute of Radiation Medicine, Beijing, 100850, People’s Republic of ChinaĬorrespondence: Haifeng Song Yi Wang, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, People’s Republic of China, Tel +86 10 81139169, Fax +86 10 81139169, Email īackground: Extracellular vesicles (EVs) are considered a promising drug delivery platform. ![]()
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