Strong π–π Stacking Stabilized Nanophotosensitizers: Improving Tumor Retention for Enhanced Therapy for Large Tumors in Mice

Abstract Conventional photosensitizers (PSs) often show poor tumor retention and are rapidly cleared from the bloodstream, which is one of the key hindrances to guarantee precise and efficient photodynamic therapy (PDT) in vivo. In this work, a photosensitizer assembly nanosystem that sharply enhances tumor retention up to ≈10 days is present. The PSs are synthesized by meso‐substituting anthracene onto a BODIPY scaffold (AN‐BDP), which then self‐assembles into stable nanoparticles (AN‐BDP NPs) with amphiphilic block copolymers due to the strong intermolecular π–π interaction of the anthracene. Additionally, the incorporated anthracene excites the PSs, producing singlet oxygen under red‐light irradiation. Although AN‐BDP NPs can completely suppress regular test size tumors (≈100 mm³) by one‐time radiation, only 12% tumor growth inhibition rate is observed in the case of large‐size tumors (≈350 mm³) under the same conditions. Due to the long‐time tumor retention, AN‐BDP NPs allow single‐dose injection and three‐time light treatments, resulting in an inhibition rate over 90%, much more efficient than single‐time radiation of conventional clinically used PSs including chlorin‐e6 (Ce6) and porphyrin with poor tumor retention. The results reveal the importance of long tumor retention time of PSs for efficient PDT, which can accelerate the clinical development of nanophotosensitizers.