Mesenchymal stem cell-derived exosomes as cell-free therapeutics: mechanistic insights and engineering strategies for liver disease treatment

Liver diseases pose a global health crisis, with liver transplantation remaining the only definitive therapy yet constrained by donor scarcity and complications. Mesenchymal stem cells (MSCs), emerging as stromal cells with immunomodulatory and regenerative capacities, face translational challenges. By contrast, MSC-derived exosomes (MSC-Exos) offer a cell-free approach with lower immunogenicity, minimal tumorigenic risk, and intrinsic hepatic tropism, mediating intercellular communication via protein and microRNA (miRNAs) cargo. To provide a focused synthesis, this review establishes a unified four-pillar framework of MSC-Exos mechanisms across liver pathologies, including (i) maintaining immunological-stromal homeostasis, (ii) reprogramming metabolic circuitry, (iii) determining cell fate, and (iv) intercepting oncogenic signaling. We further discuss advances in engineered MSC-Exos from preparation and application, aiming at enabling precision delivery and the mechanism-to-translation process. While MSC-Exos represent a transformative frontier in hepatology, addressing heterogeneity, scalable production, and cargo standardization remains critical to accelerate clinical translation.