Nanomedicine-mediated co-expression of a PD-1 blockade agent and CXCL9 synergizes T cell infiltration and activation...

Considerable progress has been made in cancer immunotherapy with the use of immune checkpoint blockade (ICB). However, its clinical efficacy remains limited due to poor T cell infiltration in solid tumors. Here, we engineered a co-expression plasmid-based gene nanomedicine to drive tumor cells to simultaneously secrete the single-chain variable fragment of an antibody targeting programmed cell death protein 1 (αPD-1 scFv, a PD-1 blocking agent) and C-X-C Motif Chemokine Ligand 9 (CXCL9, a T cell chemokine). The gene nanomedicine showed a synergistic effect on enhancing the migration and the cytotoxicity of CD8⁺ T cells in vitro and in vivo. With its dual functions, the growth of subcutaneous melanoma was effectively inhibited, and the survival time of melanoma-bearing mice was prolonged. This study provides a synergistic strategy for improving the therapeutic efficacy of immune checkpoint blockade through nanoparticle-delivered nucleic acid drugs to modulate the tumor microenvironment.