Engineered B. clausii extracellular vesicle-mediated homologous recombination impairment promotes the maintenance treatment efficacy of Olaparib in non-BRCA-mutated pancreatic cancer

Olaparib (Ola) mediated maintenance therapy is regarded as the most important way to prolong the survival period of pancreatic cancer patients after chemotherapy. However, it only has a “synthetic lethal” effect on patients with BRCA mutations. This is because in tumors non-BRCA mutations, the homologous recombination repair (HRR) function still exists. Interference with the core protein RAD51 in the BRCA pathway can lead to defects in HRR, making patients with non-BRCA mutations sensitive to Ola treatment, which is expected to broaden the adaptation range of Ola. In this study, Bacillus Clausii ( B. clausii ) was utilized to obtain the engineered extracellular vesicles (eBEVs) carrying RAD51 siRNA and expressing G3-C12 polypeptide by transforming the co-expression plasmid, which will be used for embedding Ola. Therefore, a new type of oral drug delivery system eBEVs-Ola co-carrying Ola and siRNA was successfully constructed. Its gastrointestinal protection and intestinal epithelial crossing properties enable oral administration, while the G3-C12 targeting function enable pancreatic cancer concentration. After cell entry, RAD51 siRNA specifically silenced RAD51 to block HRR, and Ola simultaneously acted on the PARP enzyme and jointly inhibited DNA damage repair, thereby sensitizing non-BRCA-mutated pancreatic cancer cells to Ola through a synthetic lethal interaction. The results showed that eBEVs-Ola exhibited good targeting and maintenance therapeutic effects in the mouse model of human pancreatic tumor xenotransplantation, and had no obvious toxicity. eBEVs-Ola, as a safe and effective oral-administered drug delivery system, may provide a potential strategy for the maintenance treatment of patients non-BRCA mutations.