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Bioorthogonally surface-edited extracellular vesicles based on metabolic glycoengineering for CD44-mediated targeting of inflammatory diseases.

ABSTRACT: Extracellular vesicles (EVs) are essential mediators in intercellular communication that have emerged as natural therapeutic nanomedicines for the treatment of intractable diseases. Their therapeutic applications, however, have been limited by unpredictable in vivo biodistribution after systemic administration. To control the in vivo fate of EVs, their surfaces should be properly edited, depending on the target site of action. Herein, based on bioorthogonal copper-free click chemistry (BCC), surface-edited EVs were prepared by using metabolically glycoengineered cells. First, the exogenous azide group was generated on the cellular surface through metabolic glycoengineering (MGE) using the precursor. Next, PEGylated hyaluronic acid, capable of binding specifically to the CD44-expressing cells, was labelled as the representative targeting moiety onto the cell surface by BCC. The surface-edited EVs effectively accumulated into the target tissues of the animal models with rheumatoid arthritis and tumour, primarily owing to prolonged circulation in the bloodstream and the active targeting mechanism. Overall, these results suggest that BCC combined with MGE is highly useful as a simple and safe approach for the surface modification of EVs to modulate their in vivo fate.

SUBMITTER: Lim GT

PROVIDER: S-EPMC7953464 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Bioorthogonally surface-edited extracellular vesicles based on metabolic glycoengineering for CD44-mediated targeting of inflammatory diseases.

Lim Gyeong Taek GT You Dong Gil DG Han Hwa Seung HS Lee Hansang H Shin Sol S Oh Byeong Hoon BH Kumar E K Pramod EKP Um Wooram W Kim Chan Ho CH Han Seungsu S Lee Sangho S Lim Seungho S Yoon Hong Yeol HY Kim Kwangmeyung K Kwon Ick Chan IC Jo Dong-Gyu DG Cho Yong Woo YW Park Jae Hyung JH

Journal of extracellular vesicles 20210312 5

Extracellular vesicles (EVs) are essential mediators in intercellular communication that have emerged as natural therapeutic nanomedicines for the treatment of intractable diseases. Their therapeutic applications, however, have been limited by unpredictable in vivo biodistribution after systemic administration. To control the in vivo fate of EVs, their surfaces should be properly edited, depending on the target site of action. Herein, based on bioorthogonal copper-free click chemistry (BCC), sur ...[more]

PMID: 33738083

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Project description:ObjectiveExtracellular vesicle (EV) therapy has been shown to mitigate inflammation in animal models of acute myocardial ischemia/reperfusion. This study evaluates the effect of EV therapy on inflammatory signaling in a porcine model of chronic myocardial ischemia and metabolic syndrome.MethodsYorkshire swine were fed a high-cholesterol diet for 4 weeks to induce metabolic syndrome, then underwent placement of an ameroid constrictor to the left circumflex artery to induce chronic myocardial ischemia. Two weeks later, pigs received intramyocardial injection of either saline (control) (n = 6) or EVs (n = 8). Five weeks later, pigs were put to death and left ventricular myocardial tissue in ischemic and nonischemic territories were harvested. Protein expression was measured with immunoblotting, and macrophage count was determined by immunofluorescent staining of cluster of differentiation 68. Data were statistically analyzed via Wilcoxon rank-sum test.ResultsEV treatment was associated with decreased expression of proinflammatory markers nuclear factor kappa B (P = .002), pro-interleukin (IL) 1ß (P = .020), and cluster of differentiation 11c (P = .001) in ischemic myocardium, and decreased expression of nuclear factor kappa B in nonischemic myocardium (P = .03) compared with control. EV treatment was associated with increased expression of anti-inflammatory markers IL-10 (P = .020) and cluster of differentiation 163 (P = .043) in ischemic myocardium compared with control. There were no significant differences in expression of IL-6, tumor necrosis factor alpha, arginase, HLA class II histocompatibility antigen DR alpha chain, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha, or phosphorylated nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha in ischemic myocardium or pro-IL1ß, IL-6, tumor necrosis factor alpha, IL-10, or nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha in nonischemic myocardium of EV-treated pigs compared with control. There were no differences in macrophage count in ischemic myocardium between EV-treated pigs and control.ConclusionsIn the setting of metabolic syndrome and chronic myocardial ischemia, intramyocardial EV therapy attenuates proinflammatory signaling.

Dataset Information

Bioorthogonally surface-edited extracellular vesicles based on metabolic glycoengineering for CD44-mediated targeting of inflammatory diseases.

Publications

Bioorthogonally surface-edited extracellular vesicles based on metabolic glycoengineering for CD44-mediated targeting of inflammatory diseases.

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