Chirality-Driven Immune Checkpoint Modulation by Chiral Iridium(III) Nanoparticles

Immune checkpoint inhibitors (ICIs) have brought revolutionary therapeutic opportunities to advanced cancers. However, the insufficient accuracy of ICIs necessitates urgent advancements in precise targeting. Herein, leveraging the high compatibility of chiral configurations with chiral biomolecules, we constructed a pair of metal-centered chiral iridium(III) nanoparticles Δ-IrBMS8-NPs and Λ-IrBMS8-NPs featuring the BMS-8 moiety to enhance the chiral adaptability with immune checkpoint biomacromolecules while avoiding the use of nanocarriers. The resulting chiral nanoparticles demonstrate markedly distinct chirality-dependent biological activities. Specifically, Δ-IrBMS8-NPs achieve a 129-fold enhancement in tumor targeting, driven by the stereoselective recognition and binding of Δ-IrBMS8-NPs to tumor-specific PD-L1. This elevated targeting accuracy of Δ-IrBMS8-NPs with PD-L1 subsequently results in significantly enhanced anticancer immune responses in vivo, especially in activating the response to cytokine pathways in dendritic cells (DCs) and the recruitment of effector CD8⁺ T cells to remodel the tumor microenvironment. This work pioneers the discovery of nanoscale metal-centered chirality in precisely targeting immune checkpoints and highlights the pivotal role of delta configurations in enhancing anticancer immune responses, paving the way for the future rational design of effective metal-based immunotherapies.