A novel exosome based therapeutic intervention against neuroendocrine prostate cancer

Abstract Neuroendocrine prostate cancer (NEPC) is a highly lethal variant of castration-resistant prostate cancer (CRPC) with poor survival rates. Current treatment options for NEPC are limited to highly toxic platinum drugs highlighting the urgent need for new therapies. This study aimed to develop a novel therapeutic approach using engineered exosomes against NEPC. Exosomes were modified to target CEACAM5, an NEPC surface antigen, by attaching CEACAM5 antibodies to HEK293T exosomes. These exosomes were loaded with drugs inhibiting EZH2 and the androgen receptor (AR) as recent research shows a persistent role of AR in NEPC wherein it plays a concerted role with EZH2 in driving neuronal gene programs. In vitro experiments with NEPC cell lines demonstrated that CEACAM5-targeted exosomes were specifically taken up by NEPC cells, leading to reduced cellular viability and decreased expression of neuronal markers. Further in vivo tests using a NEPC patient-derived xenograft model (LuCaP145.1) showed significant tumor regression in mice treated with engineered exosomes compared to control mice receiving IgG-labeled exosomes. These results suggest that CEACAM5-engineered exosomes hold promise as a targeted therapy for NEPC. Importantly, our exosome engineering strategy is versatile and can be adapted to target various surface antigens in prostate cancer and other diseases.