Youthful-state extracellular vesicles for targeted therapy of intervertebral disc degeneration: resolving inflammation and pyroptosis through NF-κB suppression and NLRP1 inactivation.

Intervertebral disc degeneration pathogenesis involves chronic inflammation and cell death, highlighting the need for targeted therapeutic strategies. Extracellular vesicles (EVs) have emerged as promising bioactive materials for designing therapeutic approach. In this study, we demonstrate that youthful-state EVs (Y-EVs) outperform aged donor-derived EVs (O-EVs) in resolving inflammatory cascades within nucleus pulposus (NP) cells. EVs from young rats significantly suppressed TNF-α-induced inflammation in NP cells by reducing pro-inflammatory cytokine secretion, inhibiting extracellular matrix catabolism, and ameliorating rat disc degenerationin vivo. Mechanistically, CD55 enrichment in Y-EVs attenuated NF-κB pathway activation, thereby disrupting inflammatory transcriptional programs. CD55 knockdown abrogated the anti-inflammatory efficacy of Y-EV, confirming its functional necessity. Besides, we identified thioredoxin (TRX) as a critical suppressor of NLRP1 inflammasome activation via direct protein binding, which inhibited NP cell pyroptosis. Crucially, CD55 in Y-EVs facilitated TRX-mediated NLRP1 suppression, whereas O-EVs failed to upregulate TRX or suppress the NLRP1 inflammasome. This study highlights the age-dependent functional divergence of EV bioactivity and establishes CD55 as a key determinant of their therapeutic superiority. The TRX-NLRP1 interaction represents a novel target for disc degeneration intervention, positioning youthful-state EVs as an optimized bioactive material for disc regeneration strategies.