Agonal cell resuscitation strategy to promote tissue repair.

Overactive lytic regulated cell death (RCD) causes excessive inflammation and impairs tissue repair. Current strategies rely on small-molecule inhibitors targeting the initiation of lytic RCD but these show off-target effects and reduced pro-repair factor release. During lytic RCD, a transitional agonal stage exists between initiation and terminal death, during which cells either proceed to terminal death or undergo resuscitation. Here, we found that agonal cells actively upregulated uptake of extracellular vesicles (EVs), and internalised EVs fused with the plasma membrane via SNARE complexes to enhance membrane repair. We demonstrated that enhancing the membrane repair capacity of agonal cells through artificially prepared EV-mimetic nano-platelet vesicles (NPVs) effectively promoted their resuscitation. Moreover, resuscitated cells secreted substantial amounts of prostaglandin E2 and N1-Acetylspermidine to further promote tissue repair. Our therapeutic strategy for lytic RCD-related delayed tissue repair is based on EV-mediated membrane repair and aims to establish a pro-regenerative niche using NPVs that can drive agonal cell resuscitation.