Ligand‐Tethered Extracellular Vesicles Mediated RNA Therapy for Liver Fibrosis

Abstract Liver fibrosis poses a significant global health burden, in which hepatic stellate cells (HSCs) play a crucial role. Targeted nanomedicine delivery systems directed at HSCs have shown immense potential in the treatment of liver fibrosis. Herein, a bioinspired material, engineered therapeutic miR‐181a‐5p (a miRNA known to inhibit fibrotic signaling pathways) and targeted moiety hyaluronic acid (HA) co‐functionalized extracellular vesicles (EVs) are developed. HA is incorporated onto the surface of EVs using DSPE‐PEG as a linker, allowing preferential binding to CD44 receptors, which are overexpressed on activated HSCs. Our results confirmed enhanced cellular uptake and improved payload delivery, as evidenced by the increased intracellular abundance of miR‐181a‐5p in activated HSCs and fibrotic livers. HA‐equipped EVs loaded with miR‐181a‐5p (DPH‐EVs@miR) significantly reduce HSC activation and extracellular matrix (ECM) deposition by inhibiting the TGF‐β/Smad signaling pathway, thus alleviating the progression of liver fibrosis. Additionally, DPH‐EVs@miR improves liver function, ameliorates inflammatory infiltration, and mitigates hepatocyte apoptosis, demonstrating superior hepatic protective effects. Collectively, this study reports a prospective nanovesicle therapeutic platform loaded with therapeutic miRNA and targeting motifs for liver fibrosis. The biomarker‐guided EV‐engineering technology utilized in this study provides a promising tool for nanomedicine and precision medicine.