Extracellular vesicle-based targeted protein degradation platform for multiple extracellular proteins.

Targeted protein degradation (TPD) is an emerging therapeutic approach that enables the degradation of undruggable targets via intracellular degradation systems. Extracellular vesicles (EVs) have shown potential to act as next-generation TPD platforms. However, the molecular mechanism underlying their degradation remains unknown, which restricts their application in TPD. In this study, we found that the autophagy-mediated lysosomal pathway was the major route by which EVs were degraded. MAP1LC3B recognized the LIR motifs of SQSTM1 and induced the degradation of EVs in the autophagy pathway. Based on the EV degradation mode, we developed an EV-based targeted protein degradation platform (EVTPD) using EVs loaded with the LIR motif of SQSTM1 as a degradation signal. Additionally, target protein-binding domains were integrated into the EVTPD to capture target proteins. EVTPD selectively degraded extracellular proteins without requiring receptors on target cells. Furthermore, dual-targeting EVTPD effectively degraded both TNF-α and IL-1β and exhibited potent anti-inflammatory effects in rat and goat models of intervertebral disc degeneration. This study has established a modular EV-based TPD strategy with multi-targeting potential.