Cell-surface photochemistry mediated calcium overload for synergistic tumor therapy

Calcium (Ca²⁺) is essential for mitochondrial homeostasis and function coordination, particularly in cancer cells that metabolize frequently to sustain their growth. Photochemistry mediated calcium overload has attracted lots of attention as an effective way to achieve tumor suppression. Herein, we developed a photonanomedicine to synergistically induce calcium overload via cell-surface photochemistry and thus tumor suppression. Specifically, the photosensitizer, protoporphyrin IX (PpIX) was loaded onto upconversion nanoparticles (UCNP), which was subsequently modified by a polymer bearing photo-crosslinking cinnamate (CA) groups. The resulting nanoparticle was further functionalized by anti-CD20 aptamers (Apt), to give photonanomedicine. The interaction between CD20 receptors and anti-CD20 aptamers allowed photonanomedicine to accurately attach onto the Raji cell surface after an intravenous injection. Following the local application of a 980 nm NIR laser, the photonanomedicine was able to capture the NIR light and convert it into ultraviolet (UV) light. On one hand, the converted UV light led the crosslinking of cinnamate groups in photonanomedicine, further stimulating the clustering of CD20 receptors and causing Ca²⁺ influx. On the other hand, the UV light could simultaneously excited PpIX to generate reactive oxygen species (ROS) in situ to break down the integrity of cell membrane and lead to an influx of Ca²⁺. The synergistic Ca²⁺ overload mediated by photonanomedicine exhibited an enhanced and superior anti-tumor efficacy. We believe this photonanomedicine expands the toolbox to manipulate intracellular Ca²⁺ concentration and holds a great potential as an anti-tumor therapy.