Pathological Microenvironment‐Remodeling Nanoparticles to Alleviate Liver Fibrosis: Reversing Hepatocytes‐Hepatic Stellate Cells Malignant Crosstalk

During the onset and malignant development of liver fibrosis, the pernicious interplay between damaged hepatocytes and activated hepatic stellate cells (HSCs) induce a self-perpetuating vicious cycle, deteriorating fibrosis progression and posing a grave threat to public health. The secretions released by damaged hepatocytes and activated HSCs interact through autocrine or paracrine mechanisms, involving multiple signaling pathways. This interaction creates a harsh microenvironment and weakens the therapeutic efficacy of single-cell-centric drugs. Herein, a malignant crosstalk-blocking strategy is prompted to remodel vicious cellular interplay and reverse pathological microenvironment to put an end to liver fibrosis. Collagenases modified, bardoxolone and siTGF-β co-delivered nanoparticles (C-NPs/BT) are designed to penetrate the deposited collagen barriers and further regulate the cellular interactions through upregulating anti-oxidative stress capacity and eliminating the pro-fibrogenic effects of TGF-β. The C-NPs/BT shows successful remodeling of vicious cellular crosstalk and significant disease regression in animal models. This study presents an innovative strategy to modulate cellular interactions for enhanced anti-fibrotic therapy and suggests a promising approach for treating other chronic liver diseases.