A review of engineering hyaluronic acid-ZIF based nanomaterials for multifunctional disease treatment: Current status and future perspectives

The hyaluronic acid (HA)-surface-modified zeolitic imidazolate frameworks (ZIFs) nanoplatform enables active targeting by specifically binding to the CD44 receptor highly expressed on tumor and inflammatory cells. Additionally, the high concentration of hyaluronidase in the lesion microenvironment under weakly acidic conditions progressively degrades the HA shell layer by layer, triggering the dissociation of the ZIF framework and release of therapeutic agents. Meanwhile, the hydrophilic HA layer forms a hydration barrier that inhibits non-specific protein adsorption, enhancing systemic drug delivery efficiency. This platform has evolved into a multifunctional nano-system suitable for drug delivery, biological imaging, and catalytic therapy, applicable in synergistic treatment scenarios for various diseases including malignancies, bacterial infections, skin wound healing, and osteoarticular injuries. Focusing on HA-functionalized ZIFs (HA-ZIFs), this study systematically elucidates the mechanisms of HA modification on interface interactions and compares the effects of different ZIF frameworks and molecular weight of HA on targeting efficacy, biocompatibility, and synergistic therapeutic outcomes. The application mechanisms of HA-ZIFs are reviewed in modular sections across multimodal cancer therapy, integrated tumor diagnosis/treatment, antimicrobial action against drug-resistant bacteria, chronic wound repair, osteoarthritis, and ischemic tissue regeneration, with particular emphasis on chemodynamic, photodynamic/photothermal, and immunomodulatory synergistic pathways. Finally, key challenges hindering clinical translation are discussed, including insufficient stability of multi-functional small-molecule co-carrier systems, lack of comprehensive degradation/metabolism data and long-term toxicological profiles in large animal models, as well as uncertainties regarding prolonged in vivo accumulation and immunological risks. This review systematically examines the value of HA-ZIFs nanoplatforms in advancing clinically relevant medical technologies from an updated and structured perspective.