Tumor Microenvironment-Responsive Biodegradable Multifunctional Nanomaterials for the Explosive Release of H₂S Gas and Enhanced Tumor Therapy

H2S gas therapy has emerged as a promising “green” treatment modality for antineoplastic therapy. However, uncontrollable/inadequate gas production, single H2S gas therapy, and biosafety are still considered to be great challenges for the application of H2S gas therapy. Herein, we have developed a tumor microenvironment (TME) intelligently triggered CaS/FexS@BSA (CFB) nanoplatform with efficient biodegradability for explosive H2S release and synergistically enhanced gas/chemodynamic/Ca2+ overload/photothermal multimodal combination therapy. CFB holds an acid-responsive degradation capacity to explosively release multifunctional components including native elements of Fe2+/3+, Ca2+, and biosignaling molecules of H2S gas while remaining stable under normal physiological conditions. The released Fe2+/3+ can catalyze H2O2 to create the extremely toxic hydroxyl radical (·OH), while depleting endogenous GSH to enhance chemodynamic therapy. The simultaneously released Ca2+ is used in Ca overload-mediated antitumor therapy. The subsequent explosive generation of H2S gas leads to the apoptosis of cancer cells, synergistically enhancing the efficiency of cancer treatment. In addition, CFB is also a good photothermal agent and can effectively inhibit tumor growth and even eliminate tumors via a combination of four-modal photothermal/gas/chemodynamic/Ca2+ synergistic therapy. Therefore, this study provides a promising strategy for the design of multifunctional calcium-based H2S donors with precise control, explosive gas production, and biosafety for multimodal combination antitumor therapy.