Photo-activatable targeted hybrid extracellular vesicles for local inflammasome modulation in acute gouty arthritis

Acute gouty arthritis is driven by monosodium urate (MSU)-induced NLRP3 inflammasome activation and IL-1β release, yet local and controllable immunomodulation remains challenging. Here, we developed pFusion@EV, a photo-activatable hybrid extracellular vesicle generated by fusing engineered 293 T-derived EVs with bone marrow mesenchymal stromal cell-derived EVs (BMSC@EV). The engineered EV membrane presents a TNFR1-binding peptide and a CD9-linked photosensitive IL-10 module, and a brief ex vivo 405-nm illumination step increases IL-10-associated bioactivity before administration. In THP-1 cells, IL-10 neutralization or deletion markedly reduced STAT3 phosphorylation, whereas TNFR1 blockade or deletion of the targeting peptide partially attenuated the response, supporting IL-10-dependent and targeting-enhanced signaling. pFusion@EV reduced macrophage oxidative stress, inflammasome-associated signaling, and pyroptosis-associated phenotypes and attenuated MSU-induced matrix-catabolic and autophagy-marker changes in chondrocytes. In acute murine air-pouch and ankle models, pFusion@EV increased local retention and reduced inflammatory-cell infiltration, IL-1β-associated responses, and early cartilage-matrix changes. These findings support ex vivo-activated pFusion@EV as a locally administered vesicular platform for modulating acute gouty arthritis but long-term structural joint protection remains to be established.