Modular Membrane-Anchored Photosensitizer with Two-Photon Activated Type-I Electron Transfer for Potentiated Tumor Therapy

While Type I photosensitizers (PSs) offer significant advantages for hypoxic solid tumors due to their low oxygen dependence, clinical translation remains impeded by limited tissue penetration from short-wavelength emission, poor water dispersibility, and imprecise subcellular localization. To overcome these challenges, we engineered NPPy, a modular, membrane-anchored, and water-soluble Type I photosensitizer. This rational design integrates two key features: near-infrared (NIR) two-photon excitation (TPE) at 880 nm and specific plasma membrane targeting. The donor–π–acceptor (D–π–A) architecture endows NPPy with exceptional plasma membrane affinity, a large two-photon absorption (TPA) cross-section (2184 GM at 880 nm), and efficient superoxide anion (O 2 •– ) generation under hypoxic. Crucially, NPPy’s spatially confined reactive oxygen species production directly triggers apoptosis through plasma membrane disruption, validated by significant tumor regression in vivo. This work establishes NPPy as a versatile platform for hypoxic-tolerant photodynamic therapy (PDT) and provides a rational design blueprint for modular PSs that simultaneously address subcellular precision, deep-tissue penetration, and aqueous compatibility key hurdles in precision oncology.