A Self‐Reinforcing Nanoplatform for Highly Effective Synergistic Targeted Combinatary Calcium‐Overload and Photodynamic Therapy of Cancer

Abstract While calcium‐overload‐mediated therapy (COMT) is a promising but largely untapped therapeutic strategy, combinatory therapy greatly boosts treatment outcomes with integrated merits of different therapies. Herein, a BPQD@CaO₂‐PEG‐GPC3Ab nanoplatform is formulated by integrating calcium peroxide (CaO₂) and black phosphorus quantum dot (BPQD, photosensitizer) with active‐targeting glypican‐3 antibody (GPC3Ab), for combinatory photodynamic therapy (PDT) and COMT in response to acidic pH and near‐infrared (NIR) light, wherein CaO₂ serves as the reservoir of calcium ions (Ca²⁺) and hydrogen peroxide (H₂O₂). Navigated by GPC3Ab to tumor cells at acidic pH, the nanoparticle disassembles to CaO₂ and BPQD; CaO₂ produces COMT Ca²⁺ and H₂O₂, while H₂O₂ makes oxygen (O₂) to promote PDT; under NIR irradiation BPQD facilitates not only the conversion of O₂ to singlet oxygen (¹O₂) for PDT, but also moderate hyperthermia to accelerate NP dissociation to CaO₂ and BPQD, and conversions of CaO₂ to Ca²⁺ and H₂O₂, and H₂O₂ to O₂, to enhance both COMT and PDT. After supplementary ionomycin treatment to induce intracellular Ca²⁺ bursts, the multimodal therapeutics strikingly induce hepatocellular carcinoma apoptosis, likely through the activation of the calpains and caspases 12, 9, and 3, up‐regulation of Bax and down‐regulation of Bcl‐2 proteins. This nanoplatform enables a mutually‐amplifying and self‐reinforcing synergistic therapy.