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.

源自间充质干细胞的细胞外囊泡（EV）由于其再生和免疫调节特性而成为肝脏疾病有前途的纳米疗法。然而，吞噬细胞快速清除外源性 EV 的问题引起了人们的关注。在这里，我们探讨了蛋白电晕对两种培养条件下的 EV 的影响，在这两种条件下，从培养基中获得的特定蛋白质同时吸附在 EV 表面上。此外，通过将 EV 与血清一起孵育，模拟全身递送时蛋白冠的形成，进一步研究了蛋白冠-EV 复合模式的解析。我们的研究结果揭示了体外条件下电晕成分对电动汽车及其体内动力学的潜在影响。我们的数据表明，结合的白蛋白创建了一个 EV 签名，可以重新定位来自肝巨噬细胞的 EV。这导致肝细胞、肝窦内皮细胞和肝星状细胞的细胞摄取显着改善。这种现象可以作为一种伪装策略，通过用白蛋白预涂 EV 来制造富含白蛋白的蛋白冠-EV 复合物，从而增强肝脏中的非吞噬细胞摄取。这项工作通过定制用于肝细胞靶向和免疫逃避的蛋白电晕-EV复合物，解决了静脉注射EV用于肝脏治疗所面临的关键挑战。