Cell-to-cell communication by exosomes controls normal and pathogenic processes^1,2. Viruses can spread in exosomes and thereby avoid immune recognition³. While biogenesis, binding and uptake of exosomes are well characterized^4,5, delivery of exosome cargo into the cytoplasm is poorly understood³. We report that the phosphatidylserine receptor HAVCR1 (refs. ^6,7) and the cholesterol transporter NPC1 (ref. ⁸) participate in cargo delivery from exosomes of hepatitis A virus (HAV)-infected cells (exo-HAV) by clathrin-mediated endocytosis. Using CRISPR–Cas9 knockout technology, we show that these two lipid receptors, which interact in the late endosome⁹, are necessary for the membrane fusion and delivery of RNA from exo-HAV into the cytoplasm. The HAVCR1–NPC1 pathway, which Ebola virus exploits to infect cells⁹, mediates HAV infection by exo-HAV, which indicates that viral infection via this exosome mimicry mechanism does not require an envelope glycoprotein. The capsid-free viral RNA in the exosome lumen, but not the endosomal uncoating of HAV particles contained in the exosomes, is mainly responsible for exo-HAV infectivity as assessed by methylene blue inactivation of non-encapsidated RNA. In contrast to exo-HAV, infectivity of HAV particles is pH-independent and requires HAVCR1 or another as yet unidentified receptor(s) but not NPC1. Our findings show that envelope-glycoprotein-independent fusion mechanisms are shared by exosomes and viruses, and call for a reassessment of the role of envelope glycoproteins in infection.

外来体的细胞间通讯控制正常和致病过程^1,2。病毒可以在外泌体中传播，从而避免免疫识别³。虽然生物发生，结合和外泌体的摄取已很好地表征^4,5，外来货物运输到细胞质中的了解甚少³。我们报告说，磷脂酰丝氨酸受体HAVCR1（参考文献^6,7）和胆固醇转运蛋白NPC1（参考文献⁸）通过网格蛋白介导的内吞作用参与甲型肝炎病毒（HAV）感染细胞（exo-HAV）的外来体的货物递送。使用CRISPR–Cas9敲除技术，我们证明了这两种脂质受体在晚期内体^9中相互作用对于膜融合以及将RNA从exo-HAV传递到细胞质中是必不可少的。埃博拉病毒利用HAVCR1-NPC1途径感染细胞⁹，通过exo-HAV介导HAV感染，这表明通过这种exosome模仿机制的病毒感染不需要包膜糖蛋白。外泌体管腔中无衣壳的病毒RNA，而不是外泌体中包含的HAV颗粒的内体脱膜，主要是通过未包裹的RNA的亚甲基蓝灭活评估的外泌HAV感染性。与exo-HAV相比，HAV颗粒的感染性与pH无关，需要HAVCR1或另一个尚未鉴定的受体，但不需要NPC1。我们的发现表明外来体和病毒共有不依赖包膜糖蛋白的融合机制，并要求重新评估包膜糖蛋白在感染中的作用。