Biodegradable calcium sulfide-based nanomodulators for H2S-boosted Ca2+-involved synergistic cascade cancer therapy

Hydrogen sulfide (H2S) is the most recently discovered gasotransmitter molecule that activates multiple intracellular signaling pathways and exerts concentration-dependent antitumor effect by interfering with mitochondrial respiration and inhibiting cellular ATP generation. Inspired by the fact that H2S can also serve as a promoter for intracellular Ca2?? influx, tumor-specific nanomodulators (I-CaS@PP) have been constructed by encapsulating calcium sulfide (CaS) and indocyanine green (ICG) into methoxy poly (ethylene glycol)-b-poly (lactide-co-glycolide) (PLGA-PEG). I-CaS@PP can achieve tumor-specific biodegradability with high biocompatibility and pH-responsive H2S release. The released H2S can effectively suppress the catalase (CAT) activity and synergize with released Ca2?? to facilitate abnormal Ca2?? retention in cells, thus leading to mitochondria destruction and amplification of oxidative stress. Mitochondrial dysfunction further contributes to blocking ATP synthesis and downregulating heat shock proteins (HSPs) expression, which is beneficial to overcome the heat endurance of tumor cells and therapy exhibits highly effective tumor inhibition effect with almost complete elimination within 14-day treatment, indicating the great prospect of CaS-based nanomodulators as antitumor therapeutics.

Automated summary

Hydrogen sulfide (H2S) acts as a gasotransmitter molecule, activating intracellular signaling pathways and exerting concentration-dependent antitumor effects. By encapsulating calcium sulfide (CaS) and indocyanine green (ICG) into a biodegradable nanomodulator, researchers have achieved pH-responsive H2S release, enabling the suppression of catalase activity, abnormal Ca2?? retention, mitochondrial destruction, and oxidative stress amplification. This leads to blocked ATP synthesis and downregulated heat shock protein expression, effectively inhibiting tumor growth.