Cell-surface photochemistry mediated calcium overload for synergistic tumor therapy

Abstract 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 cell-surface photochemistry to synergistically induce calcium overload and thus tumor suppression. Specially, we synthesized a polymer bearing photo-crosslinking cinnamate groups (CA) and anti-CD20 aptamers (Apt), which was further introduced onto upconversion nanoparticles (UCNP) (AH(CA)@UCNP). Then the photosensitizer, Protoporphyrin IX (PpIX) was loaded onto AH(CA)@UCNP to give AH(CA)@UCNP-PpIX. The interaction between CD20 receptors and anti-CD20 aptamers allowed AH(CA)@UCNP-PpIX to accurately attach onto the Raji cell surface after an intravenous injection. Following the local application of a 980 nm NIR laser, the UCNP moiety was able to capture the NIR light and convert it into ultraviolet (UV) light, resulting in the crosslinking of CA, further stimulating the clustering of CD20 receptors and causing Ca2+ influx. Additionally, 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 photochemistry-mediated Ca2+ overload mediated by AH(CA)@UCNP-PpIX exhibited a synergistic and superior anti-tumor efficacy. We believe this photochemistry expands the toolbox to manipulate intracellular Ca2+ concentration and holds a great potential as an anti-tumor therapy.