An FPS-ZM1-encapsulated zeolitic imidazolate framework as a dual proangiogenic drug delivery system for diabetic wound healing

Inhibitors that target diabetes pathology-related signaling pathways have great therapeutic potential for diabetic wound healing. Metal–organic frameworks (MOFs) are increasingly popular drug delivery systems that have high loading capacity and can release their intrinsic metal ions to act as bioactive agents. In light of this, a receptor for advanced glycation end products (RAGE) inhibitor, 4-chloro-N-cyclohexyl-N-(phenylmethyl)-benzamide (FPS-ZM1), was loaded into a cobalt (Co)-based MOF (zeolitic imidazolate framework-67, ZIF-67) to fabricate FPS-ZM1 encapsulated ZIF-67 (FZ@ZIF-67) nanoparticles (NPs). As a result, FZ@ZIF-67 NPs could dually deliver Co ions and FPS-ZM1 in a controlled manner for over 14 days. Our in vitro study showed that FZ@ZIF-67 NPs not only enhanced angiogenesis by delivering Co ions but also released FPS-ZM1 to promote M2 macrophage polarization and attenuated high glucose (HG)- and/or inflammation-induced impairment of angiogenesis through RAGE inhibition. Moreover, in an in vivo study, FZ@ZIF-67 NPs markedly improved re-epithelialization, collagen deposition, neovascularization, and relieved inflammation in diabetic wounds in rats. This study not only provides a low-cost, effective, and synergistic proangiogenic bioactive agent but also demonstrates that targeting diabetes-related pathological signaling pathways is necessary to ameliorate vascularization impairment during diabetic wound healing.