Sonodynamic
therapy (SDT) has garnered extensive attention as a noninvasive treatment for deep
tumors. Furthermore,
imiquimod (
R837), an FDA-approved
toll-like receptor 7 agonist, is commonly used in clinical settings as an immune adjuvant. We prepared an activatable sonodynamic sensitizer platform (MR) based on
glutathione-sensitive
disulfide bonds linking Leu-MB, the reduced form of
methylene blue (MB), and
R837 to achieve efficient combinatory SDT and
immunotherapy for
tumors without harming normal tissues. We also used the amphiphilic
polymer C18PMH-PEG to create self-assembled MB-R837-PEG (MRP) nanoparticles for immunosonodynamic
therapy (iSDT). iSDT is a
cancer treatment that combines activatable SDT and
immunotherapy. Our iSDT demonstrated an excellent sonodynamic effect only at the
tumor site, demonstrating high specificity in killing
tumor cells when compared to SDT reported in the literature. The iSDT improves its
tumor-killing effect by inducing an immune response, which is accomplished by secreted immune adjuvants in the
tumor site. MRP was selectively activated by
glutathione in the tumor microenvironment to release MB and
R837, exhibiting excellent antitumor sonodynamic and immune responses. In addition, when combined with an α-PD-L1 antibody for
immune checkpoint blockade, this
therapy effectively inhibited
tumor metastasis. Furthermore, mice treated with iSDT and α-PD-L1 antibody did not develop
tumors even after
tumor reinoculation, indicating that long-term immune memory was achieved. The concept of sonodynamic sensitizer preparation as a next-generation iSDT based on a noninvasive synergistic therapeutic modality applicable in the near future is presented in this study.