Cu-Fe bimetallic peroxide-based nanozyme with microenvironment-triggered cascade catalysis for synergistic hydroxyl radical, nitric oxide, and oxygen generation in trimodal wound infection therapy

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Recently, chemodynamic therapy (CDT) and gas therapy (GT) have garnered significant attention for antibacterial applications. However, effectively integrating CDT and GT into a single nanocomposite for synergistic therapy remains challenging. Herein, Cu-Fe bimetallic peroxide nanoparticles (CFp)-decorated hollow polydopamine (HPDA) nanozyme (CFp/HPDA) was fabricated and used as the carrier for nitric oxide (NO) donor BNN6 loading, resulting in the NO-releasing nanozyme of CFp/HPDA@BNN6. In the acidic bacterial infection microenvironment (BIME), CFp could rapidly dissociate by releasing Cu + and Fe 2+ ions and self-supplying abundant H 2 O 2 . On one hand, the Fenton - like catalytic reaction enabled the generation of a high level of hydroxyl radical (•OH) for CDT. On the other hand, H 2 O 2 could effectively trigger BNN6 to release NO for NO-based GT. Consequently, CFp/HPDA@BNN6 exhibited remarkable antibacterial and antibiofilm activities by exerting the bimodal GT/CDT therapy. In-depth mechanism study revealed that NO synergized the antibacterial effect of •OH by promoting bacterial ferroptosis-like death. Moreover, CFp could responsively produce a substantial amount of O 2 in the BIME, which, in combination with NO, synergistically promoted wound healing by reprogramming M1-type macrophages, downregulating hypoxia-inducible factor (HIF)-1α expression and upregulating vascular endothelial growth factor (VEGF), α-SMA and CD31 expressions. In summary, CFp/HPDA@BNN6 displayed highly efficient treatment of wound infections through the trimodal therapeutic effects of •OH, NO and O 2 , offering a promising strategy for wound infection therapy.

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