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This study introduces a co\u2010delivery system of integrating nanoenzymes and gene therapeutics sequentially modified with guanidinium\u2010based polymers and macrophage membranes to achieve synergistic therapeutic effects. This co\u2010delivery system is named MACP siTNF\u2010\u03b1 nanoparticles (NPs). MACP siTNF\u2010\u03b1 nanoparticles are designed for targeted delivery to the inflamed joint site, where they are preferentially internalized by M1\u2010type macrophages and efficiently evade lysosomal degradation. Subsequently, the co\u2010delivery system operates efficiently via a self\u2010sustaining positive feedback drug release mechanism. The biomimetic nanoplatform reduces reactive oxygen species (ROS) levels and prevents glutathione (GSH) depletion. GSH degrades the polymers to release small interfering RNA (siRNA) and expose the Prussian blue (PB) nanoenzymes, which effectively scavenge ROS and restore GSH levels. This feedback loop significantly enhances the gene silencing capability and ROS scavenging efficiency of the co\u2010delivery system. In summary, MACP siTNF\u2010\u03b1 NPs can reverse macrophage ecological niche in inflammatory soils through the dual mechanism of efficiently inhibiting the expression of tumor necrosis factor\u2010alpha (TNF\u2010\u03b1) the upstream pathway of the inflammatory response, and eliminating ROS, thus realizing efficient treatment of RA.<\/jats:p>","DOI":"10.1002\/advs.202416265","type":"journal-article","created":{"date-parts":[[2025,2,22]],"date-time":"2025-02-22T03:12:21Z","timestamp":1740193941000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Biomimetic Nanoplatform for Targeted Rheumatoid Arthritis Therapy: Modulating Macrophage Niches Through Self\u2010Sustaining Positive Feedback\u2010Driven Drug Release Mechanisms"],"prefix":"10.1002","volume":"12","author":[{"given":"Huichao","family":"Xie","sequence":"first","affiliation":[{"name":"College of Pharmacy Shenzhen Technology University  Shenzhen 518118 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