Cell Membrane-Anchoring Nano-Photosensitizer for Light-Controlled Calcium-Overload and Tumor-Specific Synergistic...

Poor selectivity and unintended toxicity to normal organs are major challenges in calcium ion (Ca²⁺ ) overload tumor therapy. To address this issue, a cell membrane-anchoring nano-photosensitizer (CMA-nPS) is constructed for inducing tumor-specific Ca²⁺ overload through multistage endogenous Ca²⁺ homeostasis disruption under light guidance, i.e., the extracellular Ca²⁺ influx caused by cell membrane damage, followed by the intracellular Ca²⁺ imbalance caused by mitochondrial dysfunction. CMA-nPS is decorated by two types of functionalized cell membranes, the azide-modified macrophage cell membrane is used to conjugate the dibenzocyclooctyne-decorated photosensitizer, and the vesicular stomatitis virus glycoprotein (VSV-G)-modified NIH3T3 cell membrane is used to guide the anchoring of photosensitizer to the lung cancer cell membrane. The in vitro study shows that CMA-nPS mainly anchors on the cell membrane, and further causes membrane damage, mitochondrial dysfunction, as well as intracellular Ca²⁺ overload upon light irradiation. Synergistically enhanced antitumor efficiency is observed in vitro and in vivo. This study provides a new synergistic strategy for Ca²⁺ -overload-based cancer therapy, as well as a strategy for anchoring photosensitizer on the cell membrane, offering broad application prospects for the treatment of lung cancer.