An Arginine-Inspired Nanocomposite Enhances Tumor Oxygenation for Optimized Photodynamic Therapy.

The hypoxic, or low-oxygenation, state within the tumor microenvironment (TME) is highly detrimental to certain oxygen-dependent therapeutic approaches, particularly Type II photodynamic therapy (PDT). Current methods to enhance tumor oxygenation include utilizing perfluorocarbon-based oxygen-carrying techniques and inhibiting cellular respiration to improve the oxygen supply. However, these approaches generally suffer from a low oxygenation efficiency. To address this, we proposed an arginine cluster-mimicking nanocomposite (CP-PArg-PFC) for oxygen delivery, aimed at elevating tumor oxygenation levels and thereby optimizing the efficacy of photosensitized therapy. This nanomaterial integrates an arginine-inspired photosensitizer (CP-PArg) with an amphiphilic perfluorocarbon derivative (PEG-PFC). The arginine cluster structure leverages the high metabolic activity of tumor cells to achieve efficient, targeted accumulation in tumors. While it generates photodynamic effects, it also possesses NIR-II fluorescence imaging capabilities, making it an excellent theranostic agent. Furthermore, polymerized perfluorocarbon enables efficient and stable oxygen transport, while nitric oxide produced via enzymatic arginine degradation suppresses tumor cell respiration. This dual-mode synergistic mechanism effectively enhances tumor oxygenation and alleviates hypoxia in the TME. By employing this design strategy of oxygen-carrying nanomaterials, we successfully achieved significant improvement in tumor tissue oxygenation and performed optimized PDT on breast tumors.