Abstract：
Doxorubicin (Dox) is an anti-tumor drug with a broad spectrum, whereas the cardiotoxicity limits its further application. In clinical settings, liposome delivery vehicles are used to reduce Dox cardiotoxicity. Here, we substitute extracellular vesicles (EVs) for liposomes and deeply investigate the mechanism for EV-encapsulated Dox delivery. The results demonstrate that EVs dramatically increase import efficiency and anti-tumor effects of Dox in vitro and in vivo, and the efficiency increase benefits from its unique entry pattern. Dox-loading EVs repeat a \"kiss-and-run\" motion before EVs internalization. Once EVs touch the cell membrane, Dox disassociates from EVs and directly enters the cytoplasm, leading to higher and faster Dox import than single Dox. This unique entry pattern makes the adhesion between EVs and cell membrane rather than the total amount of EV internalization the key factor for regulating the Dox import. Furthermore, we recognize ICAM1 as the molecule mediating the adhesion between EVs and cell membranes. Interestingly, EV-encapsulated Dox can induce ICAM1 expression by irritating IFN-γ and TNF-α secretion in TME, thereby increasing tumor targeting of Dox-loading EVs. Altogether, EVs and EV-encapsulated Dox synergize via ICAM1, which collectively enhances the curative effects for tumor treatment.
摘要：
多柔比星(Dox)是一种广谱的抗肿瘤药物,而心脏毒性限制了其进一步应用。在临床环境中，脂质体递送载体用于降低Dox心脏毒性。这里,我们用细胞外囊泡（EV）代替脂质体，并深入研究了EV包裹的Dox递送机制。结果表明，EVs在体外和体内显着提高了Dox的导入效率和抗肿瘤作用，并且效率从其独特的进入模式中增加了收益。在电动汽车内在化之前，装载Dox的电动汽车重复“亲吻和奔跑”动作。一旦电动汽车接触细胞膜，Dox从电动汽车中分离出来，直接进入细胞质，导致比单一Dox更高、更快的Dox导入。这种独特的进入模式使EV和细胞膜之间的粘附而不是EV内在化的总量成为调节Dox进口的关键因素。此外，我们认为ICAM1是介导电动汽车与细胞膜粘附的分子。有趣的是,EV包裹的Dox可以通过刺激TME中IFN-γ和TNF-α的分泌来诱导ICAM1的表达，从而增加Dox负载型电动汽车的肿瘤靶向性。总之,EV和EV封装的Dox通过ICAM1协同作用，共同增强了肿瘤治疗的疗效。
