A nature-inspired nanoplatform for multi-protein targeted degradation via the autophagy-lysosome pathway

Extracellular vesicles (EVs) have emerged as key mediators of intercellular communication. However, the mechanisms governing their degradation remain poorly understood. In this study, we demonstrated that EVs are predominantly degraded via the lysosomal pathway. Mechanistically, MAP1LC3B recognizes SNX18 on the surface of endosome-escaped EVs to facilitate their sorting into the autolysosomal pathway for degradation. Leveraging this mechanism, we optimized the lysosomal sorting efficiency of EVs by surface display of LIR motifs and constructed an EV-based targeted protein degradation nanoplatform. The EV-based nanoplatform is highly modular and can be combined with monoclonal antibodies in a plug-and-play manner. It demonstrated remarkable efficiency and selectivity in degrading EGFR, PD-L1, and VEGF. Moreover, the nanoplatform demonstrated multi-targeting capability by simultaneously degrading EGFR and VEGF. Our findings uncover a previously unrecognized mechanism of EVs degradation and provide a novel strategy to harness the EVs degradation machinery as a nature-inspired nanoplatform for the degradation of multiple targeted proteins.