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This study reveals a vicious circle of ECM-cell-ECM, where increased ECM hardness activates the STING pathway in macrophages, in turn activates hepatic stellate cells (HSCs), thus enhancing ECM stiffness again and exacerbating liver fibrosis. To reverse liver fibrosis, an innovative carrier-free nanosystem capable of degrading ECM, specifically blocking the STING pathway in macrophages as well as remodeling matrix mechanical, is created. In mouse models, pharmacological STING inhibition via alkylation in macrophages, combined with ECM degradation via matrix metalloproteinases and metal ion\u2013induced macrophage polarization, reduces stromal stiffness and reverses fibrosis. Our findings underscore the antifibrotic potential of matrix mechanical remodeling, demonstrating that concurrent reduction of matrix stiffness and inhibition of STING pathway in macrophages can synergistically promote fibrosis regression. This research establishes a previously unidentified paradigm for liver fibrosis reversal.<\/jats:p>","DOI":"10.1126\/sciadv.adz4126","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T18:58:54Z","timestamp":1763578734000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":9,"title":["Matrix mechanical remodeled carrier-free nanosystem for programmable closed-loop reversal of liver fibrosis via STING alkylation"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-4331-5686","authenticated-orcid":true,"given":"Hongyun","family":"Han","sequence":"first","affiliation":[{"name":"School of Materials Science and Engineering, Tianjin Key Laboratory of Composite and Functional Materials, Tianjin University, Tianjin 300350, China."},{"name":"State Key Laboratory of Precious Metal Functional Materials, Tianjin University, Tianjin 300350, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongrun","family":"Yu","sequence":"additional","affiliation":[{"name":"School of Materials Science and Engineering, Tianjin Key Laboratory of Composite and Functional Materials, Tianjin University, Tianjin 300350, China."},{"name":"State Key Laboratory of Precious Metal Functional Materials, Tianjin University, Tianjin 300350, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxiang","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Materials Science and Engineering, Tianjin Key Laboratory of Composite and Functional Materials, Tianjin University, Tianjin 300350, China."},{"name":"State Key Laboratory of Precious Metal Functional Materials, Tianjin University, Tianjin 300350, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4417-1157","authenticated-orcid":true,"given":"Huizhen","family":"Jia","sequence":"additional","affiliation":[{"name":"School of Materials Science and Engineering, Tianjin Key Laboratory of Composite and Functional Materials, Tianjin University, Tianjin 300350, China."},{"name":"State Key Laboratory of Precious Metal Functional Materials, Tianjin University, Tianjin 300350, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenguang","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Materials Science and Engineering, Tianjin Key Laboratory of Composite and Functional Materials, Tianjin University, Tianjin 300350, China."},{"name":"State Key Laboratory of Precious Metal Functional Materials, Tianjin University, Tianjin 300350, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-55738-1"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.4c11988"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.32776"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adj3289"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/adma.202406590"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmat5024"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2024.01.034"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2021-325150"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.ade3157"},{"key":"e_1_3_2_11_2","first-page":"569","article-title":"A boronate-based modular assembly nanosystem to block the undesirable crosstalk between hepatic stellate cells and Kupffer cells","volume":"25","author":"Jia H.","year":"2023","unstructured":"H. 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