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The simultaneous application of photothermal therapy (PTT) and photodynamic therapy (PDT) offers substantial advantages in cancer treatment. However, their synergistic anticancer efficacy is often limited by tumor hypoxia, and thermotolerance induced by high expression of heat shock proteins (HSP). Fortunately, hydrogen sulfide (H2S), known for its direct cytotoxic effect on tumor cells, has been recognized for its ability to enhance PTT and PDT. The effectiveness of H2S in these therapies is challenged by its low loading efficiency, poor stability, and short diffusion distance. To address these issues, a nanoscale emulsion drop template created through the salting‐out effect is employed to construct a robust H2S delivery system. Polydopamine (PDA), chosen for its interfacial polymerization tendency and excellent photothermal conversion rate, is utilized as a carrier for the H2S donor (ADT) and Zinc phthalocyanine (ZnPc) to fabricate a novel nanomedicine termed APZ NPs. The temperature‐responsive APZ NPs are designed to release H2S during the PTT process. Elevated H2S levels promoted vasodilation, thereby enhancing the enhanced permeability and retention effect (EPR) of APZ NPs within solid tumors. This strategy effectively alleviated tumor hypoxia by disrupting the mitochondrial respiratory chain and mitigated tumor cell heat tolerance by inhibiting HSP expression. A novel and simple emulsion droplet template is prepared based on the salting‐out effect, and the hollow PDA is fabricated using the template. Furthermore, hollow PDA is designed as carriers for H2S donors and ZnPc to fabricate APZ NPs. APZ NPs can inhibit HSP protein expression and alleviate tumor hypoxia for enhancing the synergetic PTT and PDT anticancer efficacy.

Nitric oxide (NO) can play both prosurvival and prodeath roles in photodynamic therapy (PDT). The generation efficiency of peroxynitrite anions (ONOO–), by NO and superoxide anions (O2•–), significantly influenced the outcome. Reports indicated that such efficiency is closely related to the distance between NO and O2•–. Thus, in this manuscript, l-arginine (Arg) ethyl ester-modified zinc phthalocyanine (Arg-ZnPc) was designed and synthesized as a photosensitizer (PS) and NO donor. Post light irradiation, the guanido of Arg-ZnPc can be effectively oxidized by the generated reactive oxygen species (ROS) in the PDT process to release NO. Such a strategy could ensure O2•–and NO generation in the same place at the same time to guarantee effective ONOO–formation. In addition, NO has other multiple synergistic cancer treatment functions, including tumor tissue vasodilatation for drug extravasation promotion, P-glycoprotein (P-gp) downregulation for drug efflux inhibition, and glutathione depletion for cancer cell endogenous antioxidant defense destruction. In vitro and in vivo results indicated that the effective ONOO–formation and multiple functions of Arg-ZnPc could synergistically enhance its PDT activity and ensure satisfactory cancer treatment outcome.