Enhancing Photodynamic Therapy Efficacy via Photo-Triggered Calcium Overload and Oxygen Delivery in Tumor Hypoxia Management.

: Photodynamic therapy (PDT) has emerged as a promising treatment for cancer, primarily due to its ability to generate reactive oxygen species (ROS) that directly induce tumor cell death. However, the hypoxic microenvironment commonly found within tumors poses a significant challenge by inhibiting ROS production. This study aims to investigate the effect of improving tumor hypoxia on enhancing PDT. : We employed polylactic--glycolic acid (PLGA) as a delivery vector for the encapsulation of indocyanine green (ICG), a photosensitizer, and perfluorohexane (PFH), with surface labeling mannose to facilitate targeted delivery. A potential therapeutic nanoplatform was fabricated, designated as Man-PFH-ICG@PLGA. These nanospheres are capable of localizing at tumor sites and can be tracked using photoacoustic (PA) imaging. Upon laser irradiation, the ROS generated by PDT activated the transient receptor potential cation channel subfamily A member 1 (TRPA1) located on the cell membrane. This activation led to an influx of extracellular Ca and subsequently resulted in calcium overload. The excessive Ca selectively accumulated in mitochondria, disrupting the function of enzymes involved in the mitochondrial respiratory chain. This disruption inhibits cellular respiration and decreases oxygen consumption in tumor cells, ultimately contributing to the alleviation of the hypoxic microenvironment within tumors. Simultaneously, PFH exhibited a high affinity for oxygen and can deliver exogenous oxygen directly to the tumor site through simple diffusion along the concentration gradient. Both the direct and indirect mechanisms synergistically contribute to ameliorating the hypoxic conditions within tumors, thereby augmenting the efficacy of PDT. : The synergistic effect of photocontrolled calcium overload from endogenous sources and the oxygen-carrying nanoplatform alleviates tumor hypoxia, thereby enhancing the efficacy of PDT. This approach provides a new perspective on PDT.