An infection microenvironment-responsive multifunctional nanocomposite for chronic wound treatment through redox homeostasis and macrophage regulation

Due to repeated microbial infection and an immunosuppressive microenvironment, chronic wound healing can be significantly hindered. The development of multifunctional nanomaterials capable of simultaneous antibacterial and immunomodulatory effects continues to present challenges. Herein, a multifunctional nanocomposite, MXene/Cu_2-<i>x</i>O, was developed that integrates photothermal therapy (PTT), chemodynamic therapy (CDT), and sonodynamic therapy (SDT), providing tri-modal therapy for synergistic antibacterial and immunomodulatory wound healing. MXene/Cu_2-<i>x</i>O exhibited remarkable reactive oxygen species (ROS) generation through a Fenton-like reaction and ultrasound (US)-triggered <i>in situ</i> TiO₂ sensitization. In response to the weakly acidic infection microenvironment, the prepared nanocomposite could achieve robust antibacterial and anti-biofilm efficacy under near-infrared light (NIR) and US irradiation <i>via</i> synergistic ROS and hyperthermia. Concurrently, macrophages could be polarized toward the pro-inflammatory M1 phenotype, augmenting bactericidal activity with inflammatory factor secretion regulation. Additionally, hypoxia-inducible factor (HIF-1α)/vascular endothelial growth factor (VEGF)-driven angiogenesis was significantly promoted. Thus, MXene/Cu_2-<i>x</i>O markedly accelerated wound healing under NIR/US irradiation. Both <i>in vitro</i> and <i>in vivo</i> experimental results confirmed that MXene/Cu_2-<i>x</i>O exhibits excellent antibacterial and immunomodulatory capabilities and can effectively expedite infected wound healing. This work presents a paradigm for multimodal synergistic therapy in wound healing, offering inspiration for advancing chronic refractory wound treatment.