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

H 2 S gas therapy has emerged as a promising “green” treatment modality for antineoplastic therapy. However, uncontrollable/inadequate gas production, single H 2 S gas therapy, and biosafety are still considered to be great challenges for the application of H 2 S gas therapy. Herein, we have developed a tumor microenvironment (TME) intelligently triggered CaS/Fe x S@BSA (CFB) nanoplatform with efficient biodegradability for explosive H 2 S release and synergistically enhanced gas/chemodynamic/Ca 2+ overload/photothermal multimodal combination therapy. CFB holds an acid-responsive degradation capacity to explosively release multifunctional components including native elements of Fe 2+/3+, Ca 2+, and biosignaling molecules of H 2 S gas while remaining stable under normal physiological conditions. The released Fe 2+/3+ can catalyze H 2 O 2 to create the extremely toxic hydroxyl radical (·OH), while depleting endogenous GSH to enhance chemodynamic therapy. The simultaneously released Ca 2+ is used in Ca overload-mediated antitumor therapy. The subsequent explosive generation of H 2 S 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/Ca 2+ synergistic therapy. Therefore, this study provides a promising strategy for the design of multifunctional calcium-based H 2 S donors with precise control, explosive gas production, and biosafety for multimodal combination antitumor therapy.