Overcoming T Cell Exhaustion via Immune Checkpoint Modulation with a Dendrimer‐Based Hybrid Nanocomplex

Abstract 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.