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Bacteria’s antibiotic resistance is one of the major challenges in the treatment of infectious diseases. With increasing difficulty in discovering antibiotics, there is an urgent need to develop antibiotic-free therapeutic strategies to address this grand challenge. In this report, we developed a polypyrrole (PPy)-based photothermal nano-antibiotic (PTNA) for effective treatment of multidrug-resistant (MDR) bacterial infection. PTNA was fabricated by polymerizing pyrrole onto an anionic vesicle to integrate the cationic and photothermal properties of PPy for combinatory killing against bacteria. PTNA exhibits a strong photothermal effect in the NIR-II (1064 nm) biowindow, thus it is feasible for in vivo therapy due to deeper tissue penetration. Our in vitro experiments revealed that PTNA can significantly inhibit the growth of MDR bacteria (Salmonella typhimurium), alleviate inflammatory response of infected cells, and prevent …