Disrupting the Interplay between Programmed Cell Death Protein 1 and Programmed Death Ligand 1 with Spherical Nucleic Acids in Treating Cancer

[Image: see text] Disrupting the interplay between programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) is a powerful immunotherapeutic approach to cancer treatment. Herein, spherical nucleic acid (SNA) liposomal nanoparticle conjugates that incorporate a newly designed antisense DNA sequence specifically against PD-L1 (immune checkpoint inhibitor SNAs, or IC-SNAs) are explored as a strategy for blocking PD-1/PD-L1 signaling within the tumor microenvironment (TME). Concentration-dependent PD-L1 silencing with IC-SNAs is observed in MC38 colon cancer cells, where IC-SNAs decrease both surface PD-L1 (sPD-L1) and total PD-L1 expression. Furthermore, peritumoral administration of IC-SNAs in a syngeneic mouse model of MC38 colon cancer leads to reduced sPD-L1 expression in multiple cell populations within the TME, including tumor cells, dendritic cells, and myeloid derived suppressor cells. The treatment effectively increases CD8(+) T cells accumulation and functionality in the TME, which ultimately inhibits tumor growth and extends animal survival. Taken together, these data show that IC-SNA nanoconstructs are capable of disrupting the PD-1/PD-L1 interplay via gene regulation, thereby providing a promising avenue for cancer immunotherapy.