Photo‐Controlled Calcium Overload from Endogenous Sources for Tumor Therapy

Abstract Designing reactive calcium‐based nanogenerators to produce excess calcium ions (Ca 2+ ) in tumor cells is an attractive tumor treatment method. However, nanogenerators that introduce exogenous Ca 2+ are either overactive incapable of on‐demand release, or excessively inert incapable of an overload of calcium rapidly. Herein, inspired by inherently diverse Ca 2+ ‐regulating channels, a photo‐controlled Ca 2+ nanomodulator that fully utilizes endogenous Ca 2+ from dual sources was designed to achieve Ca 2+ overload in tumor cells. Specifically, mesoporous silica nanoparticles were used to co‐load bifunctional indocyanine green as a photodynamic/photothermal agent and a thermal‐sensitive nitric oxide (NO) donor (BNN‐6). Thereafter, they were coated with hyaluronic acid, which served as a tumor cell‐targeting unit and a gatekeeper. Under near‐infrared light irradiation, the Ca 2+ nanomodulator can generate reactive oxygen species that stimulate the transient receptor potential ankyrin subtype 1 channel to realize Ca 2+ influx from extracellular environments. Simultaneously, the converted heat can induce BNN‐6 decomposition to generate NO, which would open the ryanodine receptor channel in the endoplasmic reticulum and allow stored Ca 2+ to leak. Both in vitro and in vivo experiments demonstrated that the combination of photo‐controlled Ca 2+ influx and release could enable Ca 2+ overload in the cytoplasm and efficiently inhibit tumor growth.