Theory-screened Prussian blue analogues-based nanozymes for promoting diabetic wound healing via ferroptosis inhibition

Diabetes mellitus (DM) induced wound healing impairment remains a serious health problem, which can lead to limb amputation and even shorten life span. Inhibiting ferroptosis of endothelial cells has shown promise in promoting tissue repair and regeneration. However, a majority of known ferroptosis inhibitors belong to either antioxidants or iron-chelators but with poor pharmacological adherence and even serious side effects. Herein, we construct a series of Prussian blue analogues-based nanozymes as ferroptosis nano-inhibitors to simultaneously achieve highly efficient intracellular iron capture and antioxidant properties. Through computational and experimental methods, the optimized Prussian blue analogues (MPBs) with highest iron chelating efficiency and efficacy (CuPBs) are screened out and both the CuPBs and the post-chelated products have been demonstrated to exhibit reactive oxygen species (ROS)-scavenging activities. As expected, the CuPBs successfully inhibit ferroptosis in high glucose-cultured skin repair cells, thereby repairing their proliferation, migration and angiogenesis. Mechanistically, the CuPBs regulate ferroptosis by inhibiting iron accumulation and improving the antioxidant capacity of the Xc - -GPX4 system. Moreover, in a murine diabetic wound model, the CuPBs remarkably promote the wound healing by inhibiting ferroptosis and increasing the M2/M1 macrophage ratio, showing a 2-fold higher wound closure rate than deferoxamine (DFO). Collectively, our study presents a general design strategy on developing ferroptosis nano-inhibitors and provides a promising approach for treating ferroptosis-related diseases. Schematic illustration of the preparation and screening of a series of ferroptosis nano-inhibitors and multi-therapeutic mechanisms of CuPBs for diabetic wound treatment. i) The synthesis process of MPBs via controlled reaction of K 3 [Fe(CN) 6 ] with different metal precursors, with DFT and experimental screening identifying CuPBs as optimal Fe 2+ chelators through ion-exchange-driven Prussian blue nanoparticles formation. ii) CuPBs promote diabetic wound healing by ferroptosis inhibition, ROS scavenging, immunomodulation, and angiogenesis. iii) Mechanisms of CuPBs inhibiting ferroptosis of HUVECs.