Treatment of Acute Wound Infections by Degradable Polymer Nanoparticle with a Synergistic Photothermal and...

Mild-heat photothermal antibacterial therapy avoids heat-induced damage to normal tissues but causes bacterial tolerance. The use of photothermal therapy in synergy with chemodynamic therapy is expected to address this issue. Herein, two pseudo-conjugated polymers P^M123 with photothermal units and P^Fc with ferrocene (Fc) units are designed to co-assemble with DSPE-mPEG₂₀₀₀ into nanoparticle NP^M123/Fc. NP^M123/Fc under 1064 nm laser irradiation (NP^M123/Fc+NIR-II) generates mild heat and additionally more toxic ∙OH from endogenous H₂O₂, displaying a strong synergistic photothermal and chemodynamic effect. NP^M123/Fc+NIR-II gives >90% inhibition rates against MDR ESKAPE pathogens in vitro. Metabolomics analysis unveils that NP^M123/Fc+NIR-II induces bacterial metabolic dysregulation including inhibited nucleic acid synthesis, disordered energy metabolism, enhanced oxidative stress, and elevated DNA damage. Further, NP^M123/Fc+NIR-II possesses >90% bacteriostatic rates at infected wounds in mice, resulting in almost full recovery of infected wounds. Immunodetection and transcriptomics assays disclose that the therapeutic effect is mainly dependent on the inhibition of inflammatory reactions and the promotion of wound healing. What is more, thioketal bonds in NP^M123/Fc are susceptible to ROS, making it degradable with highly favorable biosafety in vitro and in vivo. NP^M123/Fc+NIR-II with a unique synergistic antibacterial strategy would be much less prone to select bacterial resistance and represent a promising antibiotics-alternative anti-infective measure.