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An M2 macrophage\u2010erythrocyte hybrid membrane\u2010camouflaged biomimetic nanosized liposome (USM[H]L) is engineered to deliver targeted self\u2010cascading bienzymes and immunomodulators to reprogram the inflammatory microenvironment in gouty rats. The cell\u2010membrane\u2010coating endow nanosomes with good immune escape and lysosomal escape to achieve long circulation time and intracellular retention times. After being uptaken by inflammatory cells, synergistic enzyme\u2010thermo\u2010immunotherapies are achieved: uricase and nanozyme degraded uric acid and hydrogen peroxide, respectively; bienzymes improved the catalytic abilities of each other; nanozyme produced photothermal effects; and methotrexate has immunomodulatory and anti\u2010inflammatory effects. The uric acid levels markedly decrease, and ankle swelling and claw curling are effectively alleviated. The levels of inflammatory cytokines and ROS decrease, while the anti\u2010inflammatory cytokine levels increase. Proinflammatory M1 macrophages are reprogrammed to the anti\u2010inflammatory M2 phenotype. Notably, the IgG and IgM levels in USM[H]L\u2010treated rats decrease substantially, while uricase\u2010treated rats show high immunogenicity. Proteomic analysis show that there are 898 downregulated and 725 upregulated differentially expressed proteins in USM[H]L\u2010treated rats. The protein\u2010protein interaction network indicates that the signaling pathways include the spliceosome, ribosome, purine metabolism, etc.<\/jats:p>","DOI":"10.1002\/adma.202304123","type":"journal-article","created":{"date-parts":[[2023,6,20]],"date-time":"2023-06-20T19:45:17Z","timestamp":1687290317000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":104,"title":["M2 Macrophage Hybrid Membrane\u2010Camouflaged Targeted Biomimetic Nanosomes to Reprogram Inflammatory Microenvironment for Enhanced Enzyme\u2010Thermo\u2010Immunotherapy"],"prefix":"10.1002","volume":"35","author":[{"given":"Ran","family":"Chen","sequence":"first","affiliation":[{"name":"College of Pharmacy Chongqing Medical University  Chongqing 400016 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Yang","sequence":"additional","affiliation":[{"name":"College of Pharmacy Chongqing Medical University  Chongqing 400016 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