Sonodynamic Therapy‐Driven Immunotherapy: Constructing AIE Organic Sonosensitizers Using an Advanced Receptor‐Regulated Strategy

Abstract Benefit from the deeper penetration of mechanical wave, ultrasound (US)‐based sonodynamic therapy (SDT) executes gratifying efficacy in treating deep‐seated tumors. Nevertheless, the complicated mechanism of SDT undeniably hinders the exploration of ingenious sonosensitizers. Herein, a receptor engineering strategy of aggregation‐induced emission (AIE) sonosensitizers (TPA‐Tpy) with acceptor (A)‐donor (D)‐A’ structure is proposed, which inspects the effect of increased cationizations on US sensitivity. Under US stimulation, enhanced cationization in TPA‐Tpy improves intramolecular charge transfer (ICT) and accelerates charge separation, which possesses a non‐negligible promotion in type I reactive oxygen species (ROS) production. Moreover, abundant ROS‐mediated mitochondrial oxidative stress triggers satisfactory immunogenic cell death (ICD), which further promotes the combination of SDT and ICD. Subsequently, subacid pH‐activated nanoparticles (TPA‐Tpy NPs) are constructed with charge‐converting layer (2,3‐dimethylmaleic anhydride‐poly (allylamine hydrochloride)‐polyethylene glycol (DMMA‐PAH‐PEG)) and TPA‐Tpy, achieving the controllable release of sonosensitizers. In vivo, TPA‐Tpy‐mediated SDT effectively initiates the surface‐exposed of calreticulin (ecto‐CRT), dendritic cells (DCs) maturation, and CD8 + T cell infiltration rate through enhanced ROS production, achieving suppression and ablation of primary and metastatic tumors. This study provides new opinions in regulating acceptors with eminent US sensitization, and brings a novel ICD sono‐inducer based on SDT to realize superior antitumor effect.