Yang Gao, Jianping Wang, Defei Hong, Chang Yang, Hua Naranmandura
Hepatocellular carcinoma (HCC) ranks as the second most lethal malignancy worldwide, presenting formidable therapeutic challenges including tumor heterogeneity, complex microenvironment, and inefficient drug delivery. Conventional therapies such as surgery, chemotherapy, and immunotherapy are limited by systemic toxicity, drug resistance, and poor targeting specificity. Mesenchymal stem cells (MSCs) have emerged as promising drug delivery vehicles, leveraging their innate tumor-homing capacity, immunomodulatory properties, and exosome-mediated cargo transport. Preclinical studies demonstrate that MSC-based systems triple drug accumulation in tumors and synergize with immunotherapy, extending survival in HCC models. This review systematically examines recent advances in MSC-based delivery systems for HCC, focusing on engineering strategies to enhance targeting precision and controlled drug release, including genetic modification, exosome engineering, and stimuli-response systems. Despite progress, challenges such as MSC heterogeneity and scalable production persist. Emerging solutions like single-cell RNA sequencing for subpopulation selection and 3D bioprinting for standardized culture are highlighted. This work provides a roadmap for developing MSC-based precision therapies, bridging translational gaps in HCC treatment.