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Here, MHTCK, a novel biomimetic nanoplatform is presented that uniquely integrates CeO\u2082 nanozymes with the anti\u2010inflammatory peptide KAFAK through the fusion of a macrophage\u2010synoviocyte membrane coating. Physicochemical characterization reveals that MHTCK maintains nanostability with a size of \u2248 200\u00a0nm and a surface charge of \u221230\u00a0mV. Compared with conventional antioxidant nanoparticles, the platform demonstrated superior cellular uptake in synoviocytes (2.8\u2010fold), chondrocytes (3.2\u2010fold), and macrophages (4.1\u2010fold). In vitro studies revealed that MHTCK effectively scavenged multiple ROS species by targeting mitochondria while preserving mitochondrial function as evidenced by the maintenance of ATP production, and promotion of M2 macrophage polarization. The biomimetic membrane coating enabled prolonged joint retention of up to 10 days postinjection through specific tissue\u2010targeting mechanisms, significantly improving pain thresholds and cartilage preservation in an OA rat model. This work demonstrates how rational integration of nanozyme technology with peptide therapeutics in a biomimetic delivery system can effectively modulate both oxidative stress and inflammation in OA, while maintaining cellular bioenergetics, providing new insights for developing targeted nanotherapeutics for inflammatory joint diseases.<\/jats:p>","DOI":"10.1002\/smll.202502677","type":"journal-article","created":{"date-parts":[[2025,5,20]],"date-time":"2025-05-20T07:32:45Z","timestamp":1747726365000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Biomimetic Nanoplatform Integrating CeO\u2082 Nanozymes and Anti\u2010Inflammatory Peptides for Osteoarthritis Therapy"],"prefix":"10.1002","volume":"21","author":[{"given":"Chengli","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Pharmacy Clinical Research Center of Integrated Traditional Chinese and Western Medicine The Affiliated Hospital of Guizhou Medical University  Guizhou 550004 P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xukun","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Clinical Research Center of Integrated Traditional Chinese and Western Medicine The Affiliated Hospital of Guizhou Medical University  Guizhou 550004 P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yilin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Clinical Research Center of Integrated Traditional Chinese and Western Medicine The Affiliated Hospital of Guizhou Medical University  Guizhou 550004 P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Zhong","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Clinical Research Center of Integrated Traditional Chinese and Western Medicine The Affiliated Hospital of Guizhou Medical University  Guizhou 550004 P. R. 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