Metal–organic framework-based therapeutic strategies for hepatocellular carcinoma: current advances and future perspectives

Liver cancer continues to be a significant global health challenge and a primary cause of cancer-related deaths globally. Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is often identified at advanced stages, hence limiting the effectiveness of conventional treatments such as chemotherapy, radiation, and surgical resection. Nanotechnology has recently emerged as a feasible approach to overcome these limitations. Metal-organic frameworks (MOFs) have attracted considerable attention in cancer nanomedicine due to their high porosity, adjustable topologies, large surface area, and potential for multifunctionalization, enabling efficient drug loading and controlled release. These attributes make MOFs useful platforms for targeted drug delivery and for enhancing the effectiveness of therapeutic approaches such as photodynamic therapy (PDT), photothermal therapy (PTT), chemodynamic therapy (CDT), radiation, and immunotherapy. Specifically, enzyme-responsive, redox-responsive, and pH-responsive metal-organic frameworks (MOFs) have been engineered to facilitate tumor microenvironment (TME)-induced drug release, therefore improving therapeutic efficacy and minimizing systemic toxicity. MOF-based nanoplatforms enhance radiotherapeutic efficacy through radiosensitization and modulation of the tumor microenvironment, while simultaneously augmenting anticancer immune responses by promoting immune activation and synergizing with immunotherapeutic approaches. This review highlights the recent progress in MOF-based nanomedicine for liver cancer treatment specifically HCC, emphasizing targeting strategies that enhance the selective accumulation of MOF nanocarriers in liver tumors, including passive targeting via the enhanced permeability and retention (EPR) effect and active targeting through ligand functionalization. The discussion covers current challenges and constraints, as well as the future outlook for the rational design and translational development of MOF-based nanotherapeutic systems.