Design of PD-1-decorated nanocages targeting tumor-draining lymph node for promoting T cell activation

Targeted delivery of immunomodulatory molecules to the lymph nodes is an attractive means of improving the efficacy of anti-cancer immunotherapy. In this study, to improve the efficacy of PD-1 blockade-based therapy, nanocages were designed by surface engineering to decorate a programmed cell death protein 1 (PD-1) that is capable of binding against programmed death-ligand 1 (PD-L1) and -ligand 2 (PD-L2). This nanocage-mediated multivalent interaction remarkably increases the binding affinity and improves the antagonistic activity compared to free soluble PD-1. In addition, with the desirable nanocage size for optimal tumor-draining lymph node (TDLN) targeting (approximately 20 nm), rapid draining and increased accumulation into the TDLNs were observed. Moreover, the interference of the PD-1/PD-L axis with ultra-high affinity in the tumor microenvironment (effector phase) and the TDLNs (cognitive phase) significantly enhances the dendritic cell-mediated tumor-specific T cell activation. This characteristic successfully inhibited tumor growth and induced complete tumor eradication in some mice. Thus, the delivery of immunomodulatory molecules with nanocages can be a highly efficient strategy to achieve stronger anti-tumor immunity.