Matrix mechanical remodeled carrier-free nanosystem for programmable closed-loop reversal of liver fibrosis via STING alkylation

Extracellular matrix (ECM) sclerosis represents a prominent feature of fibrotic disorders; however, the macrophage response to changes in matrix stiffness and its impact on fibrotic diseases remain unclear. 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–induced 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.