A Supramolecular Thermal Switch for Precision Pyroptosis via Host-Guest Recognition and Electrostatic Interactions

Cytomembrane-puncturing gasdermin (GSDM)-mediated pyroptosis activates antitumor immunity through the release of immunogenic cellular contents and proinflammatory cytokines. However, programmable and precise pyroptosis remains challenging due to the rigidity, inefficiency, and systemic toxicity of conventional inducers. Herein, a supramolecular thermal switch is engineered to enable precision pyroptosis induction. Triiodide ions (I₃ ^-) are stabilized within β-cyclodextrin (β-CD) via host-guest recognition, enhancing payload efficiency and bioavailability, while calcium ions (Ca^{2 +}), anchored on the periphery of β-CD through electrostatic Ca^{2 +}/carboxylate interactions, nucleate CaCO₃ crystal growth. The resulting CaCO₃ matrix acts as a sustained Ca²⁺ reservoir while preventing premature leakage of both Ca²⁺ and I₃ ^-. In the acidic tumor microenvironment, CaCO₃ decomposes, enabling site-specific release of I₃ ^- and Ca²⁺ via a pH-responsive disassembly mechanism. Under spatiotemporally controlled near-infrared (NIR) laser irradiation, the boron dipyrromethene (BODIPY)-based thermal switch is activated, converting biocompatible I₃ ^- into toxic iodine (I₂) and triggering a cascade of intracellular oxidative stress, mitochondrial damage and calcium buffer collapse. Synergizing with dysregulated Ca^{2 +} homeostasis, exogenous Ca^{2 +} burst induces Ca^{2 +} overload and cysteine-aspartic acid protease-3 (caspase-3)/GSDME-mediated pyroptosis, thereby connecting innate and adaptive immunity to inhibit tumor growth and metastasis. This supramolecular engineering strategy presents a promising approach for potentiating cancer immunotherapy.