Biomimetic Dual-Catalytic Nanozyme Remodels the Liver Fibrotic Microenvironment to Alleviate Fibrosis

Abstract

Activated hepatic stellate cells (HSCs) are the primary drivers of pathological extracellular matrix (ECM) accumulation in liver fibrosis. Thus, inhibiting HSC activation is crucial for treatment; however, therapeutic efficacy often falls short of expectations. A major obstacle is the hypoxic, reactive oxygen species (ROS)-rich microenvironment, which fuels persistent HSC activation and compromises long-term treatment success. Here, we developed an activated HSCs-targeted biomimetic nanozyme, HSC-HMMDN, by coating hollow mesoporous manganese dioxide (HMMDN) with membranes derived from activated HSCs to synergistically clear ROS and alleviate hypoxia. This homologous coating strategy enables precise recognition of surface adhesion molecules (such as integrins and N-cadherin) that are highly expressed on activated HSCs, ensuring targeted delivery. Once there, the nanozyme, endowed with superoxide dismutase (SOD)- and catalase (CAT)-like activities, scavenges excessive ROS, revives mitochondrial function, and suppresses the TGF-β/Smad cascade to inhibit HSC activation. In a carbon tetrachloride (CCl4)-induced liver fibrosis rat model, HSC-HMMDN significantly ameliorated fibrosis and alleviated the hypoxic microenvironment, without showing detectable toxicity. Overall, this targeted microenvironment remodeling strategy provides a new avenue for liver fibrosis therapy.