ZIF-8-Based Nanomedicine for Bone Regeneration: A Critical Appraisal of Preclinical Osteoimmunomodulatory Evidence and Translational Readiness.

Zeolitic imidazolate framework-8 (ZIF-8)-based biomaterials are increasingly investigated for bone repair because they combine cargo loading, environment-dependent degradation, surface engineering, and bioactive Zn2+ release. However, recent reviews already catalogue the multifunctional design and orthopedic applications of ZIF-8, while the directness of evidence supporting specific osteoimmunomodulatory claims remains less clear. This structured narrative review critically appraises preclinical ZIF-8 literature using a predefined evidence-classification framework that separates direct ZIF-8 evidence in bone-related models from indirect evidence derived from in vitro or non-bone studies, zinc biology, or other biomaterials, and from proposed mechanisms lacking direct validation. Macrophage-centered immunomodulation currently has the clearest direct support, including studies linking ZIF-8-containing systems to changes in inflammatory signaling and repair-associated macrophage phenotypes alongside bone regeneration. By contrast, direct evidence for local Th17/Treg regulation, neutrophil extracellular trap modulation, and broader immune-cell networks remains limited; these pathways should therefore be treated primarily as mechanistic hypotheses or future research directions. We also examine whether reported effects can be attributed to the ZIF-8 carrier itself, released Zn2+, loaded cargo, surface coatings, or composite matrices, and summarize study-level information on formulation, release conditions, dose, models, controls, immune endpoints, and regenerative outcomes. Particular attention is given to medium-dependent ZIF-8 stability, including phosphate and biological-fluid effects, dose-dependent cytotoxicity, the uncertain fate of Zn2+ and 2-methylimidazole, bone targeting versus local retention, and the scarcity of long-term pharmacokinetic, biodistribution, and large-animal data. Finally, we propose a translational-readiness framework spanning component attribution, standardized dose-release-toxicity testing, disease-specific validation, manufacturing reproducibility, sterilization, and regulatory planning. Most available evidence remains proof-of-concept and preclinical, indicating that mechanistic and safety validation should precede claims of clinical readiness.