Sonodynamical reversion of immunosuppressive microenvironment in prostate cancer via engineered exosomes

Prostate cancer (PCa) responds poorly to routine immunotherapy due to the tumor immunosuppressive microenvironment. Here, we describe an ultrasound-based drug delivery strategy to stimulate potent anti-tumor immunity via exosomes encapsulated with sonosensitizers Chlorin e6 (Ce6) and immune adjuvant R848, namely Exo^Ce6+R848. Exo^Ce6+R848 was constructed by simple co-incubation of Ce6 and R848 with HEK 293T cell-derived exosomes. The properties of exosomes were not affected after loading Ce6 and R848, and the exosomes were accumulated in the tumor site after intratumoral injection. In vitro and in vivo assays showed that ultrasonic irradiation enhanced R848-mediated DCs maturation when Exo^Ce6+R848 was engulfed by DCs, as demonstrated by the upregulated expression of CD80 and CD86. Furthermore, these engineered exosomes together with ultrasound irradiation could synergistically reprogram macrophages from an immunosuppressive M2-like phenotype to an anti-tumor M1-like phenotype, further activating effector T cells and reverting the immunosuppressive microenvironment. The exosome delivery strategy not only supplies a paradigm for overcoming side effects of systemic delivery of Ce6 and R848, but also offers an effective combination regimen of cancer immunotherapy.