Tumor-targeted AIE polymeric micelles mediated immunogenic sonodynamic therapy inhibits cancer growth and metastasis

Aggregation-induced emission luminogens (AIEgens) exhibit potent sonosensitivity in nanocarriers compared with conventional organic sonosensitizers owing to the strong fluorescence emission in the aggregated state. However, the premature drug leakage and ineffective tumor targeting of current AIE nanosonosensitizers critically restrict their clinical applications. Here, an AIEgen-based sonosensitizer (AIE/Biotin-M) with excellent sonosensitivity was developed by assembling salicylaldazine-based amphiphilic polymers (AIE-1) and 4T1 tumor-targeting amphiphilic polymers (DSPE-PEG-Biotin) for the effective delivery of salicylaldazine to 4T1 tumor tissues, aiming to mediate immunogenic SDT. In vitro, AIE/Biotin-M were highly stable and generated plentiful singlet oxygen (¹O₂) under ultrasound (US) irradiation. After AIE/Biotin-M targeted accumulation in the tumor, upon US irradiation, the generation of ¹O₂ not only led to cancer cell death, but also elicited a systemically immune response by causing the immunogenic cell death (ICD) of cancer cells. In addition to mediating SDT, AIE/Biotin-M could chelate and reduce Fe³⁺, Cu²⁺ and Zn²⁺ by salicylaldazine for inhibiting neovascularization in tumor tissues. Ultimately, AIE/Biotin-M systemically inhibited tumor growth and metastasis upon US irradiation. This study presents a facile approach to the development of AIE nanosonosensitizers for cancer SDT.