<p>Multidrug-resistant bacterial infections pose a severe threat to sepsis, where uncontrolled bacterial proliferation and the accompanying inflammatory response lead to multiorgan dysfunction. Recent clinical isolation of a super-resistant <i>Enterobacter asburiae</i> (<i>E. asburiae</i>) strain co-harboring <i>mcr-10</i> and <i>bla</i>_NDM−1 underscores the urgent need for more effective antimicrobial strategies. Herein, we develop a synergistic strategy for the chemodynamic and photothermal therapy of super-resistant <i>E. asburiae</i> using a multifunctional mesoporous nanocomposite. This nanocomposite is composed of mesoporous silica nanoparticle loaded with polymyxin B, polydopamine, and palladium nanoparticles, possessing properties including photothermal therapy, chemodynamic therapy, and drug cargo. This synergistic approach achieves bactericidal effects through localized hyperthermia, enhanced generation of reactive oxygen species, and membrane-disrupting antibiotic action at a low dose of 42.1&#xa0;µg mL⁻¹. In a murine peritonitis-sepsis model, treatment with this multifunctional mesoporous nanocomposite reduces the bacterial burden by 100%, decreases serum levels of inflammatory cytokines to normal levels, and improves the 3-day survival rate to 100%. These findings highlight a promising therapeutic strategy that leverages nanomaterial-mediated synergy to combat super-resistant pathogens.</p> Graphical Abstract <p></p>