An NIR‐II Two‐Photon Excitable AIE Photosensitizer for Precise and Efficient Treatment of Orthotopic Small‐Size Glioblastoma

The existence of residual small-size tumors after surgery is a major factor contributing to the high recurrence rate of glioblastoma (GBM). Conventional adjuvant therapeutics involving both chemotherapy and radiotherapy usually exhibit unsatisfactory efficacy and severe side effects. Recently, two-photon photodynamic therapy (TP-PDT), especially excited by the second near-infrared (NIR-II) light, offers an unprecedented opportunity to address this challenge, attributed to its combinational merits of PDT and TP excitation. However, this attempt has not been explored yet. On the other hand, the lack of high-performance photosensitizers (PSs) also hinders the progress of TP-PDT on GBM. Based on those, a robust TP-PS, termed MeTTh, is constructed intendedly through elaborately integrating multiple beneficial design strategies into a single molecule, which simultaneously achieves excellent NIR-II excitation, large absorption cross-section, aggregation-induced NIR-I emission, and prominent Type I/II reactive oxygen species generation. Aided by nanofabrication, an impressive brain structure imaging depth of 940 µm is realized. Moreover, MeTTh nanoparticles smoothly implement precise and efficient treatment of small-size GBM in vivo under a 1040 nm femtosecond laser irradiation. This study represents first-in-class using TP-PDT on GBM, offering new insights for the therapy of small-size tumors in complex and vital tissues.