T cell exhaustion, in which dysfunctional T cells are limited in
cytokine release and constrained in immune response, leads to immune escape of
cancer cells and decreased efficiency of
cancer immunotherapy. Direct regulation or blocking of programmed death 1 (PD-1) represents a promising strategy to overcome T cell exhaustion for reinvigorating anticancer immunity. Here, the construction of a 1,3-propanesultone (1,3-PS)-grafted zwitterionic
dendrimer-entrapped
gold nanoparticle platform chelated with Gd(III) (Gd-Au DENP-PS) for immune checkpoint modulation is reported. The developed Gd-Au DENP-PS possesses good stability, antifouling property, biocompatibility, and dual-mode computed tomography (CT)/magnetic resonance (MR) imaging functions, and allows for efficient packaging and serum-enhanced delivery of PD-1
siRNA to mediate PD-1 gene silencing in T cells in vitro, and also in vivo in a
melanoma-bearing mouse model and in healthy aging mice. The
dendrimer nanocomplexes or T cell-laden nanocomplexes enable suppression of
tumor growth through the generation of significant effector CD8+ and CD4+ T cells, and the
tumor immunotherapeutic potency can be further improved by combination with an
indoleamine 2,3-dioxygenase inhibitor. This study identifies a new possibility with a functional
dendrimer-based nanohybrid platform for dual-mode CT/MR imaging-guided
cancer immunotherapy via the regulation of T cell exhaustion.