Glutathione-responsive milk-derived exosomes for safe and efficient sonodynamic cancer therapy

Abstract

The encapsulation of sonosensitizers in exosomes has emerged as a potent strategy to enhance the therapeutic outcomes of sonodynamic therapy (SDT). Recently, milk-derived exosome (MExo) has gained significant attention as a scalable and cost-effective alternative to conventional exosomes derived from cell cultures. In this study, glutathione (GSH)-responsive MExos were developed to facilitate the efficient intracellular delivery of sonosensitizers (chlorin e6, Ce6) into human breast cancer cells by leveraging their elevated GSH concentrations. GSH-cleavable diselenide bond-bearing fatty amine derivative (DSe) was incorporated into MExos to achieve GSH-responsive drug release in cancer cells. DSe-incorporated MExo (DMExo) facilitated the release of Ce6 in the reductive cytoplasm. This led to enhanced generation of reactive oxygen species after ultrasound (US) treatment. As a result, Ce6-loaded DMExo triggered significant cell death in MCF-7 human breast cancer cells upon US exposure. These results demonstrate that bioreducible MExo is a safe and effective carrier for efficient SDT against cancer cells.