Chiral Au@Ag Nanoparticles Regulate Macrophage Reprogramming for Enhanced Anti‐Tumor Efficacy

ABSTRACT Chiral nanostructures exhibit unique immunomodulatory properties by engaging stereospecific recognition mechanisms within biological systems, enabling precision immune engineering. Yet the underlying mechanisms of chiral‐dependent effects on immune cells—specifically, how distinct chiral configurations activate intracellular cascades to elicit anti‐tumor effects—remain poorly understood. Here, we engineered chiral silver‐shelled gold nanoparticles (Au@Ag‐L/D NPs) with specifically tailored morphologies and plasmon‐enhanced photoresponsivity, demonstrating that chiral particles with weak optical dissymmetric factors can sufficiently elicit enantiomer‐dependent immune reprogramming. Notably, D‐enantiomers preferentially bind to scavenger receptors to disrupt lysosomal autophagy, effectively repolarizing tumor‐associated macrophages from pro‐tumorigenic M2 to antitumor M1 phenotypes. Combined with near‐infrared light‐triggered hyperthermia and ROS generation, chirality‐guided M1 polarization amplifies anti‐tumor immunity while enabling localized tumor ablation. In vivo, D NPs with photoirradiation enhanced tumor suppression in colorectal cancer models through concerted immunological microenvironment remodeling and multi‐modal tumor eradication. This study thus established precise chirality‐immunomodulation coordination, by combining phototherapy with immunotherapy to synergistically enhance tumor ablation and reverse immunosuppression.