Sonodynamic Therapy by Reactive Oxygen Species Generation-Responsive Pseudo-Semiconducting Polymer Nanoparticles Combined with a Fibroblast Growth Factor Receptor Inhibitor for Enhancing Immunotherapy in Bladder Cancer.

Sonodynamic therapy, a treatment modality recently widely used, is capable of disrupting the tumor microenvironment by inducing immunogenic cell death (ICD) and enhancing antitumor immunity during immunotherapy. Erdafitinib, an inhibitor of the fibroblast growth factor receptor, has demonstrated potential benefits for treating bladder cancer. However, Erdafitinib shows effectiveness in only a small number of patients, and the majority of patients responding positively to the medication have "immune-cold" tumors. To increase the therapeutic efficacy of Erdafitinib, we have herein developed a biodegradable pseudoconjugate polymer (PSP) with sonodynamic capabilities. Erdafitinib could be efficiently encapsulated in nanoparticles (NP-PE) prepared through the self-assembly of PSP with an oxidation-sensitive polymer (P1). Under ultrasound conditions, NP-PE effectively induced cytotoxicity by producing reactive oxygen species and further triggering ICD. Compared with Erdafitinib, NP-PE inhibited the expression of FGFR3 to a higher extent. In animal models with bladder cancer, NP-PE inhibited tumor growth, stimulated antitumor immunity, and synergized with antiprogrammed cell death-ligand 1 (aPD-L1), offering a novel approach for the treatment of bladder cancer.