M2 Macrophage Hybrid Membrane-Camouflaged Targeted Biomimetic Nanosomes to Reprogram Inflammatory Microenvironment for Enhanced Enzyme-Thermo-Immunotherapy.

Excessive inflammatory reactions caused by uric acid deposition are the key factor leading to gout. However, clinical medications cannot simultaneously remove uric acid and eliminate inflammation. An M2 macrophage-erythrocyte hybrid membrane-camouflaged biomimetic nanosized liposome (USM[H]L) was engineered to deliver targeted self-cascading bienzymes and immunomodulators to reprogram the inflammatory microenvironment in gouty rats. The cell-membrane-coating endowed 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-thermo-immunotherapies were 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 had immunomodulatory and anti-inflammatory effects. The uric acid levels markedly decreased, and ankle swelling and claw curling were effectively alleviated. The levels of inflammatory cytokines and ROS decreased, while the anti-inflammatory cytokine levels increased. Proinflammatory M1 macrophages were reprogrammed to the anti-inflammatory M2 phenotype. Notably, the IgG and IgM levels in USM[H]L-treated rats decreased substantially, while uricase-treated rats showed high immunogenicity. Proteomic analysis showed that there were 898 downregulated and 725 upregulated differentially expressed proteins in USM[H]L-treated rats. The protein-protein interaction network indicated that the signaling pathways included the spliceosome, ribosome, purine metabolism, etc. This article is protected by copyright. All rights reserved.