Targeting the hepatic stellate cell microenvironment: nanomedicine strategies for liver fibrosis therapy

Liver fibrosis, driven by hepatic stellate cells (HSCs) activation and pathological extracellular matrix (ECM) remodeling, involves dynamic crosstalk among macrophages, hepatocytes, liver sinusoidal endothelial cells (LSECs), and the fibrotic niche. In this perspective, we discuss the complex interactions among macrophages, hepatocytes, LSECs, ECM, and HSCs within the hepatic microenvironment, highlighting their role in liver fibrosis. Emerging nanomedicine strategies offer a promising solution through precision targeting, functionalization, and delivery optimization. This perspective highlights the pharmacological challenges of conventional therapies and underscores how nanomedicine overcomes biological barriers through enhanced biodistribution, reduced off-target effects, and combinatorial payload delivery. Future directions emphasize the need for patient stratification based on fibrosis etiology, the development of biomarker-guided smart nanosystems, and the clinical translation of microenvironment-remodeling approaches. By bridging mechanistic insights with cutting-edge drug delivery technologies, this work provides a roadmap for next-generation antifibrotic therapeutics.