Engineered Reverse Growth of Metastable Electron‐Rich Pd Clusters for Enhanced Catalytic/Sonodynamic/Immune Therapy

Abstract

ABSTRACT Stabilizing metastable electron‐rich metals with atomic dispersion is critical for boosting tumor microenvironment (TME)‐responsive catalysis and sonodynamic therapy (SDT), yet remains challenging. Herein, a “reverse growth” strategy is employed to kinetically trap Pd atoms from bulk Pd nanoparticles (NPs) via sub‐nano CoSe x O y ‐POM assemblies, forming atomically dispersed metastable electron‐rich Pd clusters (Ternary‐Pd). Electron delocalization at the sub‐nanoscale induces electron rearrangement in the entire sub‐nanostructure, thus enabling the acquisition of a novel electronic structure. Interestingly, the Pd clusters exhibit a more negative valence relative to 0‐valent Pd. Specifically, such low‐valent Pd clusters in an atomically dispersed state potently augment TME‐responsive catalytic reactions, exhibiting a 15‐fold enhancement in hydroxyl radical (•OH) generation for catalytic therapy, alongside enhanced hydrogen peroxide (H 2 O 2 )‐responsive oxygen (O 2 ) evolution that mitigates tumor hypoxia. Furthermore, their uniquely enriched electron density at the Pd active sites facilitates electron–hole separation, thereby potentiating SDT efficacy and resulting in a sixfold increase in singlet oxygen ( 1 O 2 ) yield. Abundant and different reactive oxygen species (ROS) induce mitochondrial oxidative stress, activating the caspase‐1/GSDMD‐mediated pyroptosis pathway. Besides, the introduced selenium (Se) doping promotes robust systemic immune responses to inhibit the growth of tumor metastases after oxidative stress.