Bioresponsive nano-antibacterials for H(2)S-sensitized hyperthermia and immunomodulation against refractory implant–related infections

There is an increasingly growing demand for nonantibiotic strategies to overcome drug resistance in bacterial biofilm infections. Here, a novel “gas-sensitized hyperthermia” strategy is proposed for appreciable bacteria killing by the smart design of a metal-organic framework (MOF)–sealed Prussian blue–based nanocarrier (MSDG). Once the biofilm microenvironment (BME) is reached, the acidity-activated MOF degradation allows the release of diallyl trisulfide and subsequent glutathione-responsive generation of hydrogen sulfide (H(2)S) gas. Upon near-infrared irradiation, H(2)S-sensitized hyperthermia arising from MSDG can efficiently eliminate biofilms through H(2)S-induced extracellular DNA damage and heat-induced bacterial death. The generated H(2)S in the biofilm can stimulate the polarization of macrophages toward M2 phenotype for reshaping immune microenvironment. Subsequently, the secretion of abundant regeneration-related cytokines from M2 macrophages accelerates tissue regeneration by reversing the infection-induced pro-inflammatory environment in an implant-related infection model. Collectively, such BME-responsive nano-antibacterials can achieve biofilm-specific H(2)S-sensitized thermal eradiation and immunomodulatory tissue remodeling, thus realizing the renaissance of precision treatment of refractory implant–related infections.