Cell Membrane‐Anchoring Nano‐Photosensitizer for Light‐Controlled Calcium‐Overload and Tumor‐Specific Synergistic Therapy

Abstract Poor selectivity and unintended toxicity to normal organs are major challenges in calcium ion (Ca 2+ ) overload tumor therapy. To address this issue, a cell membrane‐anchoring nano‐photosensitizer (CMA‐nPS) is constructed for inducing tumor‐specific Ca 2+ overload through multistage endogenous Ca 2+ homeostasis disruption under light guidance, i.e., the extracellular Ca 2+ influx caused by cell membrane damage, followed by the intracellular Ca 2+ 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 Ca 2+ overload upon light irradiation. Synergistically enhanced antitumor efficiency is observed in vitro and in vivo. This study provides a new synergistic strategy for Ca 2+ ‐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.