Metal-Organic Frameworks as Advanced Gene Delivery Vectors: Mechanisms, Functionalization, and Biomedical Applications.

Gene therapy has emerged as a transformative therapeutic strategy for addressing genetic disorders, refractory cancers, and infectious diseases; however, its clinical translation is significantly hindered by the lack of efficient, safe, and targeted gene delivery vectors. Conventional viral vectors are limited by immune rejection, narrow packaging capacity, and potential biosafety risks, while early nonviral vectors often suffer from poor targeting ability, low intracellular delivery efficiency, and insufficient protection of genetic cargo. Thus, the development of advanced gene delivery vectors is critical to overcoming these bottlenecks, safeguarding the stability and bioavailability of genetic materials, and unlocking the full therapeutic potential of gene-based therapies. Metal-organic frameworks (MOFs) are a new type of porous nanomaterial with substantial potential for use in gene delivery due to their large specific surface area, tunable pore size, good biocompatibility, and low toxicity. Here, we present a comprehensive review of MOF synthesis strategies, gene delivery mechanisms, and associated progress in biomedical applications. Genes can be effectively loaded onto MOFs through pore encapsulation, surface adsorption, covalent binding, and in situ encapsulation. Subsequently, surface functionalization methods are used to achieve precise delivery. In tumor-targeted therapy, MOFs can specifically recognize cancer cells and release genes in response to the microenvironment, thereby significantly inhibiting tumor growth. In the field of immune regulation, MOF multifunctionality supports the codelivery of genes and immune drugs, synergistically enhancing the antitumor immune response. However, challenges remain in the clinical application of MOFs, including insufficient biostability, low intracellular delivery efficiency, and potential toxicity. These challenges are expected to be addressed in the future through the development of new stable MOF materials, the optimization of surface engineering strategies, and the construction of intelligent responsive systems, yielding more precise and efficient gene therapy development.