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

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 Fe²⁺ ions and self-supplying abundant H₂O₂. 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, H₂O₂ 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 O₂ 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 O₂, offering a promising strategy for wound infection therapy.