Smart Lipid Nanoparticle that Remodels Tumor Microenvironment for Activatable H₂S Gas and Photodynamic Immunotherapy

Hydrogen sulfide (H₂S) has shown promise for gas therapy. However, it is still controversial whether H₂S 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 H₂S specifically in tumor tissues for on-demand H₂S gas and photodynamic immunotherapy. 1-JK-PS-FA enables a burst release of H₂S 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 H₂S 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 H₂S gas and photodynamic immunotherapy, effectively eradicating orthotopic breast tumors and preventing tumor metastasis and recurrence. This work showcases the capacity of H₂S to reprogram the TME to enhance H₂S gas and immunotherapy.