Applications of ZIF-8-Based Nanoplatforms in Orthopedic Diseases: Evidence Base, Mechanistic Attribution, and Translational Barriers

Orthopedic diseases severely impair the quality of life of hundreds of millions of people worldwide and impose a substantial socioeconomic burden. Conventional treatments remain limited in terms of disease-site targeting, sustained drug release, and mitigation of adverse effects. Zeolitic imidazolate framework-8 (ZIF-8), formed through the coordination of Zn2⁺ with 2-methylimidazole, has a porous structure, a high cargo-encapsulation capacity, and environment-dependent disassembly characteristics. Through the release of Zn2⁺, it may also contribute to osteogenesis, antibacterial activity, and microenvironmental modulation. Accordingly, ZIF-8 has been investigated in preclinical studies of osteosarcoma, osteoporosis, osteoarthritis, osteomyelitis, and bone defect repair. Using a structured narrative and critical approach, this review summarizes strategies for ZIF-8 preparation, drug loading, and functionalization and compares the evidence across orthopedic indications with respect to research stage, validation of stimulus responsiveness, mechanistic attribution, biosafety, and barriers to clinical translation. Current evidence is derived primarily from in vitro and small-animal studies, and no therapeutic studies in humans have been identified. Although many studies have reported pH-dependent release in vitro, few have directly measured framework disassembly, cargo release, or Zn2⁺ exposure within disease sites in vivo. In multicomponent systems, the individual contributions of the therapeutic cargo, ZIF-8 framework, Zn2⁺, and surface modifications have rarely been adequately distinguished. Data on long-term toxicity, biodistribution, and clearance also remain limited, and batch-to-batch consistency and large-scale production have not been systematically validated. Future studies should prioritize formulation-specific physicochemical characterization and the establishment of safe dose windows. They should also include component controls that distinguish the contributions of the cargo, framework, and Zn2⁺, as well as clinically relevant comparators and large-animal models. These measures are needed to determine the incremental value and translational feasibility of ZIF-8 platforms for specific orthopedic indications.