Dual-Responsive Nanoplatform: In Situ Self-Assembly Enables OFF-to-ON Photothermal Switching for Multimodal Synergistic Tumor Therapy

Abstract Photothermal therapy has attracted extensive attention in tumor treatment owing to its spatiotemporal controllability and noninvasiveness. However, the nonselective “always on” nature of traditional photothermal nanoagents together with the intrinsic thermal resistance within tumor cells has hampered the therapeutic efficacy. Herein, we developed a tumor-microenvironment-responsive transformable prenanotherapeutic platform with a polyethyleneimine (PEI)-coated tannic acid-Ca2+ chelate core and an outer shell of Fe2+-doped ZIF-90, which enabled the in situ generation of photothermal agents, synchronous activation of multiple therapeutic modalities, as well as cascaded synergistic enhancement of antitumor potency. First, degradation triggered by high-concentration adenosine triphosphate (ATP) and mild acidity within tumor cells liberated Fe2+ to catalyze hydroxyl radical (·OH) production for chemodynamic therapy. Meanwhile, the generated Fe3+ readily underwent in situ self-assembly with tannic acid to form photothermal agents, which competitively released Ca2+ and induced calcium overload. Subsequently, the dual mitochondrial destruction pathway induced by ·OH and excess Ca2+ suppressed ATP synthesis, which further downregulated the expression of heat shock protein 70 and elevated tumor cell thermosensitivity to realize mild photothermal therapy. Moreover, heat generated via photothermal agents enhanced the efficiency of Fenton-like reactions for robust ·OH accumulation, further improving the therapeutic efficacy. In vitro experiments revealed the underlying synergistic antitumor mechanism, while in vivo experiments confirmed the remarkable tumor suppression capacity of the nanomaterial. Notably, an intelligent TME-responsive “OFF-to-ON” multifunctional nanoplatform was fabricated on the basis of differential binding affinities of metal ions and polyphenols, offering a safer, more efficient and precise strategy for synergistic cancer therapy.