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细胞摄取和间充质干细胞衍生的细胞外囊泡的体内分布依赖于蛋白质冠。

Cellular uptake and in vivo distribution of mesenchymal-stem-cell-derived extracellular vesicles are protein corona dependent.

机构信息

Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London, London, UK.

Pharmacology Department, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.

出版信息

Nat Nanotechnol. 2024 Jun;19(6):846-855. doi: 10.1038/s41565-023-01585-y. Epub 2024 Feb 16.

DOI:10.1038/s41565-023-01585-y
PMID:38366223
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11186763/
Abstract

Extracellular vesicles (EVs) derived from mesenchymal stem cells are promising nanotherapeutics in liver diseases due to their regenerative and immunomodulatory properties. Nevertheless, a concern has been raised regarding the rapid clearance of exogenous EVs by phagocytic cells. Here we explore the impact of protein corona on EVs derived from two culturing conditions in which specific proteins acquired from media were simultaneously adsorbed on the EV surface. Additionally, by incubating EVs with serum, simulating protein corona formation upon systemic delivery, further resolved protein corona-EV complex patterns were investigated. Our findings reveal the potential influences of corona composition on EVs under in vitro conditions and their in vivo kinetics. Our data suggest that bound albumin creates an EV signature that can retarget EVs from hepatic macrophages. This results in markedly improved cellular uptake by hepatocytes, liver sinusoidal endothelial cells and hepatic stellate cells. This phenomenon can be applied as a camouflage strategy by precoating EVs with albumin to fabricate the albumin-enriched protein corona-EV complex, enhancing non-phagocytic uptake in the liver. This work addresses a critical challenge facing intravenously administered EVs for liver therapy by tailoring the protein corona-EV complex for liver cell targeting and immune evasion.

摘要

外泌体（EVs）来源于间充质干细胞，由于其具有再生和免疫调节特性，因此是治疗肝脏疾病的有前途的纳米药物。然而，人们对外源 EVs 被吞噬细胞快速清除表示担忧。在这里，我们探讨了蛋白冠对两种培养条件下 EVs 的影响，这两种培养条件下特定的蛋白质从培养基中同时被吸附在 EV 表面上。此外，通过用血清孵育 EVs，模拟全身给药时蛋白冠的形成，进一步研究了蛋白冠-EV 复合物的模式。我们的研究结果揭示了在体外条件下，蛋白冠组成对 EVs 的潜在影响及其体内动力学。我们的数据表明，结合的白蛋白会产生 EV 特征，从而使来自肝巨噬细胞的 EV 重新靶向。这导致肝实质细胞、肝窦内皮细胞和肝星状细胞的摄取明显增加。这种现象可以通过用白蛋白预先包被 EV 来制备富含白蛋白的蛋白冠-EV 复合物作为伪装策略来实现，从而增强肝脏中非吞噬性摄取。这项工作通过针对肝细胞膜靶向和免疫逃逸来调整蛋白冠-EV 复合物，解决了静脉内给药的 EV 治疗肝脏疾病的一个关键挑战。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b6d/11186763/6e3f1705c27c/41565_2023_1585_Fig7_ESM.jpg
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