ZIF-8 Nanodrug Delivery Systems: Construction Strategies, Functional Modifications, and Advances in Synergistic Tumor...

Conventional chemotherapeutic agents are commonly hampered by off-target toxicity and multidrug resistance. Although nanoscale delivery systems can enhance targeting and controlled release, they are frequently constrained by insufficient drug-loading capacity. Zeolitic imidazolate framework-8 (ZIF-8), a metal-organic framework self-assembled from Zn²⁺ and 2-methylimidazole, features pH-triggered degradability, high drug payload, and favorable biocompatibility. This review systematically evaluates ZIF-8-based cancer therapeutic platforms, comparing synthetic routes (batch preparation versus scalable production), drug-loading strategies (one-pot versus impregnation methods), and functional modification approaches (PEGylation, folic acid conjugation, hyaluronic acid decoration, RGD peptide grafting, and cell-membrane coating) with respect to their efficacy in overcoming current limitations. The core section highlights multimodal combination therapies integrating chemotherapy, photothermal/photodynamic therapy, gene therapy, and immunotherapy. Furthermore, we discuss translational obstacles, including heterogeneous enhanced permeability and retention (EPR) effects, manufacturing reproducibility, and regulatory hurdles, with the goal of comprehensively unleashing the potential of ZIF-8. We conclude that ZIF-8 represents a versatile platform; however, its clinical application necessitates a paradigm shift from empirical design to mechanism-driven engineering, alongside standardized scalable production.