Breaking Defense Barriers: A Self‐Assembled Nanocascade Potentiating Triphasic Sono‐Immunotherapy for MDR Bacterial Infections

ABSTRACT Multidrug‐resistant (MDR) bacteria pose a formidable challenge to conventional sonodynamic therapy (SDT) due to their sophisticated defense mechanisms, including antioxidant systems, efflux pumps, and the ability to create an immunosuppressive microenvironment. To address these barriers, we propose a “three‐phase” sono‐immunotherapy strategy using a supermolecular nanoplatform co‐assembled from trivalent bismuth (Bi 3+ ), natural sonosensitizer hypericin (Hy), and immunopotentiator Astragali polysaccharide (APS). In the pre‐SDT priming phase, Bi 3+ leverages its high thiophilicity to deplete glutathione while impairing bacterial efflux pumps via NADH dehydrogenase inhibition. Concurrently, its Fe(III)‐mimetic property suppresses the key antioxidant enzyme of superoxide dismutase, collectively disarming bacterial redox defenses and enhancing Hy accumulation. During SDT execution, ultrasound triggers Hy to generate a sustained, potent reactive oxygen species storm within this preconditioned microenvironment, effectively killing bacteria. Subsequently, in the post‐SDT immunization phase, APS reprograms the local immunosuppressive milieu. Together with SDT‐generated bacterial debris, it synergistically promotes dendritic cell maturation and effector T cell expansion, enabling immune‐mediated clearance of residual bacteria. In a murine model of MDR Pseudomonas aeruginosa pneumonia, this integrated approach achieved near‐complete infection resolution. By sequentially orchestrating defense disruption, oxidative detonation, and immune activation, our precision‐engineered SDT paradigm offers a highly effective solution for intractable MDR infections.