Targeting Xkr8 via nanoparticle-mediated in situ co-delivery of siRNA and chemotherapy drugs for cancer immunochemotherapy

Activation of scramblases is one of the mechanisms that regulates the exposure of phosphatidylserine to the cell surface, a process that plays an important role in tumour immunosuppression. Here we show that chemotherapeutic agents induce overexpression of Xkr8, a scramblase activated during apoptosis, at the transcriptional level in cancer cells, both in vitro and in vivo. Based on this finding, we developed a nanocarrier for co-delivery of Xkr8 short interfering RNA and the FuOXP prodrug to tumours. Intravenous injection of our nanocarrier led to significant inhibition of tumour growth in colon and pancreatic cancer models along with increased antitumour immune response. Targeting Xkr8 in combination with chemotherapy may represent a novel strategy for the treatment of various types of cancers. Downregulation of specific proteins named scramblases might enhance tumour immunosuppression. In this paper the authors first show that the scramblase Xrk8 is overexpressed in tumour cells upon treatment with chemotherapeutics, and then develop a nanomedicine platform for co-delivery of a cancer prodrug and an siRNA directed against the Xrk8 gene, showing therapeutic effect and enhanced immune response in animal tumour models.