Lysosome-Targeting Nanochimeras Attenuating Liver Fibrosis by Interconnected Transforming Growth Factor-β Reduction and Activin Receptor-Like Kinase 5 Degradation

Liver fibrosis, characterized by excessive extracellular matrix (ECM) deposition, is predominantly driven by activated hepatic stellate cells (HSCs) through the TGF-β-Smad2/3 signaling pathway. A critical barrier to effective treatment has been the compensatory upregulation of the receptors, which often limits the efficacy of targeted TGF-β inhibition strategies. Our current study introduces a lysosomal targeting degradation chimera (MAP) composed of an antioxidative polydopamine (PDA) nanoparticle conjugated to the ligands specifically targeting ALK5, a TGF-β receptor I, and cation-independent mannose 6-phosphate receptor (CI-M6PR). Notably, CI-M6PR is highly upregulated on the surface of the activated HSCs. These MAPs preferentially accumulated in the fibrotic liver tissues, reduced TGF-β production by scavenging reactive oxygen species, and simultaneously recognized the activated HSCs to facilitate targeted lysosomal degradation of ALK5. The interconnected dual-enhanced mechanisms effectively inhibited the TGF-β-Smad2/3 signaling pathway in HSCs, thus diminishing ECM secretion and attenuating liver fibrosis. Together, the current findings, substantiated by in vitro and in vivo studies, demonstrate potent antifibrotic capacities of MAPs, marking an essential advancement in lysosome-targeting degradation technology for liver fibrosis treatment and expanding potential therapeutic options for this intractable condition.