NIR-II imaging guided on-site size variable clustered nanosystem to potentiate sonodynamic therapy in deep-seated tumors

The insufficient enrichment and penetration of sonosensitizers in the tumor site hamper the antitumor efficiency of sonodynamic therapy (SDT). Herein, tumor-acidity and photothermal controlled nanosystems (NTTD), which coloaded a new type of sonosensitizers, Na₃TiF₆ NPs and second near-infrared (NIR-II) emissive AIEgen (T1), have been developed to achieve highly efficient SDT/photothermal therapy (PTT) in deep-seated tumors. On one hand, NTTD includes ultrasmall Na₃TiF₆ NPs with increased oxygen vacancies, narrow bandgap (2.82 eV) and preferrable absorption capability of H₂O and O₂ molecules, guaranteeing powerful generation of reactive oxygen species (ROS) under US stimulation. On the other hand, with the assistance of the acidic/photothermal responses and deep penetrated NIR-II fluorescence imaging (up to 7 mm), NTTD undergo in situ “two-step” size transformation to achieve enhanced retention and penetration of sonosensitizers in tumor area with high spatiotemporal controllability. In 4T1 tumor model, compared to passive targeting participated NTT group, NTTD elongated the tumor retention time to 60 h and revealed enhanced imaging signal (∼2.4 fold). Further photoirradiation of NTTD assisted ∼4.5-fold enhancement of penetration ability. SDT/PTT synergies have evoked significant ROS generation and tumor inhibition rate of 75.2 % in vivo. This study presents an innovative strategy to exploit novel nano-sonosensitizers with precisely improved tumor accumulation and penetration.