Synchronous Sterilization and Macrophage Regulation for Treating Multidrug-Resistant <i>Pseudomonas aeruginosa</i>-Infected Pneumonia

The emergence of multidrug-resistant bacteria and persistent inflammatory responses have exacerbated the therapeutic difficulty of bacteria-infected pneumonia. There is an urgent need to find new strategies for synchronous sterilization and inflammation regulation for pneumonia. Herein, we developed maleimide-modified and alantolactone (Ala)-loaded copper indium selenide nanoparticles (ACIS NPs) to achieve near-infrared II (NIR-II) light-triggered photodynamic immunotherapy for multidrug-resistant <i>Pseudomonas aeruginosa</i>-infected pneumonia. After intranasal administration, they can quickly penetrate the mucus layer and then target <i>P. aeruginosa</i> and attach to its biofilm, achieving bacterial inactivation and biofilm elimination under NIR-II light irradiation. Simultaneously, ACIS NPs can also release Ala at the lesion site. They can not only stimulate the maturation of phagolysosomes in macrophages to increase phagocytosis efficiency but also downregulate the expression of NF-κB to reduce inflammatory cytokines and relieve the inflammatory level, thus promoting the polarization of macrophages toward an anti-inflammatory phenotype. Both <i>in vitro</i> and <i>in vivo</i> experiments have demonstrated that ACIS NPs can accumulate in lung tissues for killing <i>P. aeruginosa</i> and regulating macrophages, exhibiting high therapeutic efficacy against bacteria-infected pneumonia. This study demonstrates the potential of ACIS NPs as an alternative to traditional antibiotics, offers hope against bacterial resistance and the inhibition of biofilm formation, regulates the disordered inflammatory environment of the body, and provides a new strategy for bacteria-infected pneumonia therapy.