Smart Lipid Nanoparticle that Remodels Tumor Microenvironment for Activatable H 2 S Gas and Photodynamic Immunotherapy.

Hydrogen sulfide (H 2 S) has shown promise for gas therapy. However, it is still controversial whether H 2 S can remodel the tumor microenvironment (TME) and induce robust antitumor immunity. Here, a tumor-targeting and TME-responsive "smart" lipid nanoparticle ( 1 -JK-PS-FA) is presented, which is capable of delivering and releasing H 2 S specifically in tumor tissues for on-demand H 2 S gas and photodynamic immunotherapy. 1 -JK-PS-FA enables a burst release of H 2 S in the acidic TME, which promptly reduces the embedded organic electrochromic materials and consequently switches on near-infrared fluorescence and photodynamic activity. Furthermore, we found that high levels of H 2 S can reprogram the TME by reducing tumor interstitial fluid pressure, promoting angiogenesis, increasing vascular permeability, ameliorating hypoxia, and reducing immunosuppressive conditions. This leads to increased tumor uptake of 1 -JK-PS-FA, thereby enhancing PDT efficacy and eliciting strong immunogenic cell death during 808 nm laser irradiation. Therefore, 1 -JK-PS-FA permits synergistic H 2 S gas and photodynamic immunotherapy, effectively eradicating orthotopic breast tumors and preventing tumor metastasis and recurrence. This work showcases the capacity of H 2 S to reprogram the TME to enhance H 2 S gas and immunotherapy.