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Here, we report a genetically engineered chondrocyte-mimetic nanoplatform (termed HKL-GECM@MPNPs) comprising a honokiol (HKL)\u2013loaded mitochondrion-targeting nanoparticle core coated with an interleukin-1 receptor type 2 (IL-1R2)\u2013overexpressing chondrocyte membrane. HKL-GECM@MPNPs fuse with OA chondrocytes, transferring IL-1R2 onto the plasma membrane and reprogramming the inflamed microenvironment through IL-1\u03b2 blockade. Mitochondrion-targeting cores then directly deliver HKL to restore mitochondrial sirtuin-3 in OA chondrocytes, reprogramming the cells\u2019 pathological phenotype. Intra-articular injection of HKL-GECM@MPNPs in OA mice reduces inflammation, alleviates joint pain, and mitigates cartilage damage through a synergistic effect. Moreover, HKL-GECM@MPNPs effectively reverse cartilage degeneration in human OA cartilage explants. This approach highlights the potential of HKL-GECM@MPNPs to combine IL-1\u03b2 blockade and mitochondrial sirtuin-3 restoration as a promising strategy for OA treatment.<\/jats:p>","DOI":"10.1126\/sciadv.adv4238","type":"journal-article","created":{"date-parts":[[2025,7,25]],"date-time":"2025-07-25T17:58:38Z","timestamp":1753466318000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":29,"title":["Genetically engineered chondrocyte-mimetic nanoplatform attenuates osteoarthritis by blocking IL-1\u03b2 and restoring sirtuin-3"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0153-5168","authenticated-orcid":true,"given":"Caifeng","family":"Deng","sequence":"first","affiliation":[{"name":"Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China."},{"name":"Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya 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