Ultrasound‐Recharged Sub‐Nanometer Palladium Catalysts for on‐Demand and Self‐Terminating Bioorthogonal Prodrug Activation in Cancer Therapy

ABSTRACT Bioorthogonal catalysis holds great promise for precision cancer therapy, yet its clinical translation is critically hindered by the lack of reliable control over catalytic activity. Uncontrolled “always‐on” catalysis or irreversible activation prevents timely termination, making it difficult to confine prodrug activation within a safe therapeutic window. To address this challenge, we developed an ultrasound‐recharging‐regulated closed‐loop bioorthogonal system integrating on‐demand activation, enhanced catalytic performance, and self‐termination, enabling precise in vivo prodrug activation. Mechanistically, pyroelectric polarization of BaTiO ₃ induces deposition of sub‐nanometer Pd clusters whose catalysis is initially silenced by rapid oxidative passivation. Upon ultrasound stimulation, the piezoelectric BaTiO ₃ core generates a built‐in electric field that reduces surface Pd ²⁺ to catalytically active Pd ⁰ , thereby activating bioorthogonal reactions while promoting charge separation and reactive oxygen species generation. Simultaneously, piezoelectric screening charges accelerate interfacial electron transfer, significantly enhancing catalytic kinetics. Crucially, rapid repassivation after ultrasound cessation leads to complete catalytic deactivation, establishing a closed bioorthogonal cycle following a single stimulus. In vitro and in vivo studies demonstrate that the activated species induce immunogenic cell death while avoiding side effects from persistent catalysis. This work presents a safe, controllable, and efficient paradigm for bioorthogonal catalytic therapy, advancing its clinical translation.