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

TL;DR

A new nanosystem reverses liver fibrosis by reducing matrix stiffness and blocking a key immune pathway in macrophages.

Contribution

A carrier-free nanosystem is introduced to simultaneously degrade ECM and inhibit the STING pathway for fibrosis reversal.

Findings

Increased ECM stiffness activates the STING pathway in macrophages, worsening liver fibrosis.

STING inhibition and ECM degradation synergistically reduce fibrosis in mouse models.

Matrix mechanical remodeling offers a new paradigm for treating fibrotic diseases.

Abstract

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.

A matrix mechanical remodeled carrier-free nanosystem was designed to reverse liver fibrosis through an ECM-cell-ECM closed-loop.

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