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

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_xO_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 (H₂O₂)-responsive oxygen (O₂) 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 (¹O₂) 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.