Photo-Controlled Calcium Overload from Endogenous Sources for Tumor Therapy

Designing reactive calcium-based nanogenerators to produce excess calcium ions (Ca²⁺) in tumor cells is an attractive tumor treatment method. However, nanogenerators that introduce exogenous Ca²⁺ are either overactive incapable of on-demand release, or excessively inert incapable of an overload of calcium rapidly. Herein, inspired by inherently diverse Ca²⁺-regulating channels, a photo-controlled Ca²⁺ nanomodulator that fully utilizes endogenous Ca²⁺ from dual sources was designed to achieve Ca²⁺ 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 Ca²⁺ nanomodulator can generate reactive oxygen species that stimulate the transient receptor potential ankyrin subtype 1 channel to realize Ca²⁺ 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 Ca²⁺ to leak. Both in vitro and in vivo experiments demonstrated that the combination of photo-controlled Ca²⁺ influx and release could enable Ca²⁺ overload in the cytoplasm and efficiently inhibit tumor growth.