Enhanced Sonodynamic Therapy and Radiotherapy Efficacy: Modified Polyethylene Glycol–Bismuth Trioxide Nanoplatform for Targeted Tumor Treatment

This study develops a novel multifunctional nanoplatform, modified polyethylene glycol-bismuth trioxide (mPEG-Bi₂O₃), synthesized via vacuum ball milling followed by ultrasonic liquid-phase exfoliation and surface PEGylation, to enhance the synergistic effects of sonodynamic therapy (SDT) and radiotherapy (RT). Characterization revealed that mPEG-Bi₂O₃ exhibits a thin-layered nanosheet structure (hydrodynamic size: 239.28 ± 4.32 nm; lattice spacing: 0.29 nm) and a zeta potential of -33.64 ± 0.80 mV. Notably, the nanoplatform demonstrated exceptional colloidal stability in physiologically relevant media, maintaining consistent size and surface charge over 7 d in serum-containing medium, which confirms the effectiveness of the PEG coating for biomedical applications. XPS analysis confirmed a mixed Bi³⁺/Bi⁵⁺ oxidation state, and deconvolution of the O 1s spectrum quantified the oxygen vacancy content at 11.02%, confirming a defect-rich structure. Successful PEG grafting was verified by Fourier transform infrared spectroscopy and quantified by thermogravimetric analysis, showing a grafting content of ~13.59 wt %. Under low-intensity focused ultrasound (LIFU), mPEG-Bi₂O₃ significantly enhanced reactive oxygen species generation, leading to a marked reduction in intracellular glutathione levels. In vitro cytotoxicity studies demonstrated favorable selectivity, with lower toxicity toward normal endothelial cells compared to 4T1 cancer cells, and the combination of mPEG-Bi₂O₃ and LIFU induced apoptosis in 4T1 cells. In vivo studies showed that intravenous administration of mPEG-Bi₂O₃ in tumor-bearing mice resulted in peak tumor accumulation at 24 h (0.17 ± 0.03 %ID/g), correlating with a significant 87.82% ± 4.77% reduction in tumor volume after 14 d of treatment when combined with LIFU and RT (10 Gy), superior to dual-modality treatments. Immune profiling indicated enhanced dendritic cell maturation, increased tumor-infiltrating CD8⁺ T cells, and reduced regulatory T cells, demonstrating immune microenvironment remodeling. Collectively, mPEG-Bi₂O₃ presents a surface-engineered strategy for potent SDT-RT synergy with demonstrated biosafety, showing promising potential for solid tumor treatment.