A photodriven nano-extinguisher alleviates acute bacterial infections via toll-like receptor 4-regulated immune response.

Pattern recognition receptors on immune cells play essential roles in detecting pathogen-associated molecular patterns and initiating downstream immune defense cascades. Toll-like receptor-4, a key member of the PRR family, regulates macrophage-mediated innate immune responses; however, its dysregulation due to excessive activation often exacerbates inflammatory processes. Herein, we report a Toll-like receptor-4-targeted nano-extinguisher designed to combat acute pneumonia caused by multidrug-resistant Pseudomonas aeruginosa infection. This innovative nanoplatform integrates bacterial capture ligands, a photothermal agent, and a Toll-like receptor-4 signaling inhibitor. Upon near-infrared light irradiation, the nano-extinguisher generates localized hyperthermia, leading to bacterial death through disruption of membrane integrity. Moreover, the thermal-triggered release of the Toll-like receptor-4 signaling inhibitor enables dual immunomodulation by simultaneously regulating macrophage polarization and scavenging reactive oxygen species. The nano-extinguisher significantly alleviated the pathological progression of infection-induced acute pneumonia in our experiments. By combining photothermal antibacterial activity with spatiotemporal immunomodulation, this nanoengineered system offers a promising translational strategy for the treatment of acute bacterial infections and concurrent mitigation of Toll-like receptor-4-mediated immunopathology. STATEMENT OF SIGNIFICANCE: TLR4, which is crucial for initiating innate immunity via pathogen detection, often exacerbates inflammation when hyperactivated. We developed TLR-4-targeted nano-extinguishers to combat multidrug-resistant Pseudomonas aeruginosa-induced pneumonia. This system integrates bacterial capturing, photothermal therapy, and TLR-4 inhibition. Photo-driven localized hyperthermia disrupts bacterial membranes while thermally releasing the inhibitor, thereby achieving simultaneous macrophage polarization modulation and reactive oxygen species scavenging, effectively mitigating infection-induced pneumonia. By integrating precision photothermal sterilization with spatiotemporal immunoregulation, our nanoengineered strategy addresses both bacterial eradication and TLR-4-mediated immunopathology, offering translational potential for the treatment of acute infections.