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Current therapies fail to halt or reverse its progression, largely because of the limited understanding and lack of targeted therapies for key mechanisms. This study aimed to integrate single\u2010cell transcriptomics with clinical validation to construct a comprehensive cellular atlas for IVDD. The study uncovered a pronounced fibrotic barrier in degenerative tissues that severely impeded drug delivery and identified pyroptosis in nucleus pulposus cells driven by stimulator of interferon genes (STING)\u2010mediated activation of multiple inflammatory pathways. To overcome these challenges, this study developed a self\u2010enriching nanocarrier (Motor@TA\u2010small interfering ribonucleic acid [siRNA]) that catalyzes hydrogen peroxide to generate asymmetric bubble propulsion, thereby enabling selective penetration into degenerated tissues without accumulation in healthy tissues. Tannic acid forms a hydrogen\u2010bonded network with the siRNA, thereby enhancing its stability and delivery efficiency. The siRNA precisely targets the STING pathway to block inflammation\u2013pyroptosis signaling at its source. Both the in vitro and in vivo results demonstrated that the nanocarrier possessed excellent biocompatibility and significantly delayed the progression of IVDD. This study presents a synergistic mechanism\u2013target\u2013material strategy that integrates pathological insight with advanced nanocarrier design, offering a promising platform for personalized IVDD therapy.<\/jats:p>","DOI":"10.1002\/adma.202516405","type":"journal-article","created":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T13:50:22Z","timestamp":1762350622000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["A Single\u2010Cell\u2010Inspired Self\u2010Enrichment Therapeutic Strategy Delays Intervertebral Disc Degeneration by Inhibiting Pyroptosis"],"prefix":"10.1002","volume":"38","author":[{"given":"Hao","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Spine Surgery The Third Xiangya Hospital Central South University  Changsha Hunan 410013 P. R. 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