细胞外囊泡（EVs）含有100多种蛋白质。至今未证明EVs蛋白质是否能作为蛋白质网络的“组织者”，从而产生与EV生成细胞不同的新生物学效应。本研究以此为概念证明，EV-G12D突变KRAS能够作为领袖形成蛋白质复合物，通过Fn1/IL-17A/FGF21轴促进肺部炎症和肿瘤生长。从机理上看，与来自EV生成细胞的细胞质来源的G12D突变KRAS复合物相比，EV-G12D突变KRAS通过纤维连接蛋白-1（Fn1）与一组细胞外囊泡因子相互作用，驱动EV受体细胞中IL-17A/FGF21炎症通路的激活。我们发现：（i）去除EV-Fn1会导致多种炎症细胞因子（包括IL-17A）减少；（ii）诱导IL-17A会促进肺部炎症，随之而来的是IL-17A介导的FGF21在肺部的诱导；以及（iii）IL-17受体KO小鼠消除了EV-G12D突变KRAS复合物介导的肺部炎症。这些发现建立了EV功能的新概念，并具有潜在的临床应用价值，可用于治疗EV介导的疾病过程。© 2023年作者。由Wiley Periodicals，LLC代表国际细胞外囊泡学会出版的《细胞外囊泡》杂志。

Extracellular vesicles (EVs) contain more than 100 proteins. Whether there are EVs proteins that act as an 'organiser' of protein networks to generate a new or different biological effect from that identified in EV-producing cells has never been demonstrated. Here, as a proof-of-concept, we demonstrate that EV-G12D-mutant KRAS serves as a leader that forms a protein complex and promotes lung inflammation and tumour growth via the Fn1/IL-17A/FGF21 axis. Mechanistically, in contrast to cytosol derived G12D-mutant KRAS complex from EVs-producing cells, EV-G12D-mutant KRAS interacts with a group of extracellular vesicular factors via fibronectin-1 (Fn1), which drives the activation of the IL-17A/FGF21 inflammation pathway in EV recipient cells. We show that: (i), depletion of EV-Fn1 leads to a reduction of a number of inflammatory cytokines including IL-17A; (ii) induction of IL-17A promotes lung inflammation, which in turn leads to IL-17A mediated induction of FGF21 in the lung; and (iii) EV-G12D-mutant KRAS complex mediated lung inflammation is abrogated in IL-17 receptor KO mice. These findings establish a new concept in EV function with potential implications for novel therapeutic interventions in EV-mediated disease processes.© 2023 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.