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 strengthen ICG-induced photothermal performance. Such a H₂S-boosted Ca²⁺-involved tumor-specific 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.

硫化氢 (H ₂ S) 是最近发现的气体递质分子，可激活多种细胞内信号通路，并通过干扰线粒体呼吸和抑制细胞 ATP 生成发挥浓度依赖性抗肿瘤作用。受 H ₂ S 也可以作为细胞内 Ca ²⁺流入的促进剂这一事实的启发，通过将硫化钙 (CaS) 和吲哚菁绿 (ICG) 封装到甲氧基中构建了肿瘤特异性纳米调节剂 (I-CaS@PP)聚（乙二醇）-b-聚（丙交酯-共-乙交酯）（PLGA-PEG）。I-CaS@PP 可实现肿瘤特异性生物降解性，具有高生物相容性和 pH 响应性 H ₂释放。释放的H ₂ S可有效抑制过氧化氢酶(catalase, CAT)活性，并与释放的Ca ²⁺协同促进细胞内Ca ²⁺的异常滞留，从而导致线粒体破坏和氧化应激放大。线粒体功能障碍进一步有助于阻断​​ATP合成和下调热休克蛋白（HSPs）表达，这有利于克服肿瘤细胞的耐热性和增强ICG诱导的光热性能。这样的 H ₂ S-boosted Ca ²⁺-涉及的肿瘤特异性治疗表现出高效的肿瘤抑制作用，在 14 天的治疗中几乎完全消除，表明基于 CaS 的纳米调节剂作为抗肿瘤治疗剂的巨大前景。