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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-mPEG 2000 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 H 2 O 2 , 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., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Photothermal therapy based on conjugated polymers represents a promising antibacterial strategy but still possesses notable limitations. Herein, degradable pseudo conjugated polymers (PCPs) containing photothermal molecular backbones and reactive oxygen species (ROS)-sensitive thioketal bonds are designed. Triphenylphosphine (PPh 3 ) is introduced into PCPs to generate phosphonium-based PCPs (pPCPs), which further assembled with hyaluronic acid into pPCP nanoparticles (pPCP-NPs). pPCP-NPs with quaternary phosphonium cations selectively anchor on and destroy bacterial cell membranes through electrostatic action. Under 1064 nm laser irradiation, pPCP-NPs (pPCP-NPs/+L) produce near-infrared-II (NIR-II) photothermal antibacterial effect, thereby killing bacteria in a sustained manner. pPCP-NPs are readily degraded upon ROS abundant at infection sites, therefore exhibiting enough biosafety. pPCP-NPs/+L display an almost 100% bacterial inhibition rate in vitro and resultin a nearly complete recovery of bacteria-induced mouse wounds. A further metabolomics analysis denotes that pPCP-NPs/+L work in a concerted way to induce bacterial DNA damage, inhibit bacterial carbon/nitrogen utilization and amino acid/nucleotide synthesis. Taken together, degradable pPCP-NPs with both NIR-II photothermal effect and cationic phosphonium structural bacteriostasis provide a new avenue for antibiotics-alternative anti-infection therapy., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Clinical therapy of multidrug resistant (MDR) bacteria‐induced deep‐tissue infections such as pneumonia is highly challenging. Ultrasound (US)‐induced sonodynamic therapy (SDT) is a promising strategy for treatment of deep‐tissue diseases given the strong tissue penetration of US. Here, ZIF‐8‐derived carbon@TiO2 nanoparticles (ZTNs) are developed as inhalable sonosensitizers for bacterial pneumonia. ZTNs upon US irradiation exhibit an excellent efficacy to produce reactive oxygen species (ROS) and thereby to kill Gram‐negative MDR bacteria in vitro. Taking advantage of aerosolized intratracheal inoculation, ZTNs can be precisely delivered to lung infection sites, and display an effective SDT‐based elimination of Gram‐negative MDR bacteria in the lung infection models of immunocompetent or immunodeficient mice. Particularly, ZTNs upon US irradiation give a 100% survival rate in the severely immunodeficient NOD/SCID mice with a lethal bacterial pneumonia. In addition, ZTNs have no obvious toxicity at both cellular and animal levels. Metal–organic‐framework‐derived nanoparticles as safe and efficient inhalable sonosensitizer have a great potential to be used for the clinical antibiotics‐alternative treatment of MDR bacterial pneumonia. This study presents a new paradigm for SDT‐based treatment of deep‐tissue bacterial infections, and will expand the nanomedicine application of inorganic sonosensitizers. [ABSTRACT FROM AUTHOR]