Nanomedicine integrating the lipidic derivative of 5-fluorouracil, miriplatin and PD-L1 siRNA for enhancing tumor therapy

Immunosuppressive microenvironments present critical problems in clinical chemotherapy. To regulate the tumor immune microenvironment for enhancing antitumor effect, a combination of immune checkpoint inhibitors (ICIs) with chemotherapeutics has been applied clinically. In this study, miriplatin (MiPt), the lipidic derivative of 5-fluorouracil (Fu-OA), as well as the programmed death ligand 1 (PD-L1) target siRNA (siPD-L1) were integrated into Lip-Pt/Fu@siPD-L1 nanoparticles (NPs) for chemo-immunotherapy. In vitro results showed that Lip-Pt/Fu@siPD-L1 NPs could exhibit effective siRNA gene silencing and promote the phagocytosis of tumor cells by macrophages. Furthermore, in vivo results revealed that Lip-Pt/Fu@siPD-L1 NPs showed significantly higher anti-tumor efficiency than that of the physical mixing of MiPt, 5-fluorouracil, and Lip@siPD-L1 NPs (delivery of siPD-L1 by liposomes). The best anti-tumor efficiency of Lip-Pt/Fu@siPD-L1 NPs resulted from the synergistic immunotherapeutic effects of MiPt and siPD-L1 based on the inhibition of CD47 expression and the downregulation of PD-L1 in tumor cells, which elicited a robust anti-tumor immune response through the activation of macrophage phagocytosis and immune checkpoint inhibition. The Lip-Pt/Fu@siPD-L1 NPs provide a potential strategy for tumor chemo-immunotherapy.