Multifunctional metal complex-based gene delivery for tumour immune checkpoint blockade combination therapy

Immune checkpoint blocking based on the PD-1/PD-L1 pathway has shown exciting results in various types of cancer. However, due to the off-target effect of PD-1/PD-L1 blocker, low tumour immunogenicity and tumour immunosuppressive microenvironment, a significant proportion of patients do not benefit from this treatment. Here, we constructed a novel multifunctional metal complex Fe/PEI-Tn by the coordination of polyethyleneimine (PEI) with Fe³⁺ and the modification of bifunctional peptides Tn containing the cell penetrating peptide (TAT) and nuclear localisation signal peptide (NLS), which was coated with hyaluronic acid (HA) to prolong the circulation time in vivo. Fe/PEI-Tn can condensate PD-L1 trap plasmid (pPD-L1 trap) and mediate PD-L1 trap protein expression in tumour tissues in situ, thus blocking the PD-1/PD-L1 pathway. Besides, Fe/PEI-Tn metal complex itself can act as an immune adjuvant to activate macrophages, reverse the phenotype of pro-tumour M2-type macrophages, and promote anti-tumour immunity. Meanwhile, Fe/PEI-Tn treatment can induce damage in tumour cells and release tumour-specific antigens into tumour microenvironment, thus stimulating anti-tumour immune response. Studies showed that HA/Fe/PEI-Tn/pPD-L1 trap complexes could promote the immune activation of tumour tissues and effectively delay tumour growth. This strategy provides a new direction for tumour combination therapy based on PD-1/PD-L1 blockade.