A glutathione-activated bismuth-gallic acid metal-organic framework nano-prodrug for enhanced sonodynamic therapy of breast tumor

Sonodynamic therapy is a promising, noninvasive, and precise tumor treatment that leverages sonosensitizers to generate cytotoxic reactive oxygen species during ultrasound stimulation. Gallic acid (GA), a natural polyphenol, possesses certain anti-tumor properties, but exhibits significant toxicity toward normal cells, limiting its application in cancer treatment. To overcome this issue, we synthesized a bismuth-gallic acid (BGA), coordinated metal-organic framework (MOF) nano-prodrug. Upon encountering glutathione (GSH), BGA gradually dissociated and depleted GSH, releasing GA, which had anti-tumor effects. As an MOF with semiconductor properties, BGA primarily produced superoxide anion radical upon ultrasound excitation. After the release of GA, GA generated superoxide anion radical and further produced high toxic singlet oxygen under ultrasound stimulation, while further oxidizing and consuming GSH, enhancing sonocatalytic performance. Additionally, the released GA induced cell cycle arrest, ultimately leading to apoptosis. Our results revealed that BGA, as a GSH-activated, metal-polyphenol MOF nano-prodrug, showed potential for use in breast tumor sonodynamic therapy, providing a novel strategy for precise tumor treatment.