Piezoelectric Amplification of Cascade Enzymatic Catalysis and Nanomotor Propulsion for Synergistic Electrodynamic‐Starvation Tumor Therapy

While dynamic and starvation therapies offer potential to mitigate tumor resistance and systemic toxicity, their clinical translation is critically hampered by tumor hypoxia, insufficient enzyme activity, and the dense extracellular matrix that obstructs therapeutic agent accumulation and distribution. Herein, Janus piezoelectric nanoparticles are engineered with spatial enzyme conjugation to amplify cascade enzyme catalysis, overcome delivery barriers, and synergize piezoelectrodynamic-stravation therapy.

Abstract

Piezoelectrodynamic therapy (PEDT) is compromised by hypoxia dilemma of tumors, while starvation therapy is constrained by insufficient enzyme activities. To address these challenges, Janus piezoelectric nanoparticles (NPs) are proposed to spatially immobilize glucose oxidase (GOx) and catalase (CAT), enabling piezoelectric potential-amplified enzyme activities and synergistic PEDT-starvation tumor therapy. Here hollow barium titanate (hBT) NPs are synthesized using SiO₂ templates, followed by partial Au deposition via the Pickering emulsion-masking method to create Janus hBT@Au NPs, which are then conjugated with GOx and CAT on opposing sides to yield C-hBT@Au-G NPs. The hollow structure of hBT enhances flexibility and deformation under ultrasonication, while Schottky heterojunctions with Au layers promote charge carrier transfer, amplifying piezoelectric effects and free electron transfer to boost GOx activities. Piezoelectric field-enhances selective tumor cell internalization of NPs and PEDT generation of reactive oxygen species (ROS), coupled with self-propagated GOx/CAT cascades, intensify tumor cytotoxicities and deplete intracellular adenosine triphosphate. The Janus architecture, ultrasonic cavitation, and O₂ generation collaboratively drive robust propulsion for efficient NP accumulation and deep ROS penetration into tumor tissues, thereby achieving full tumor suppression with negligible systemic toxicity. This design overcomes delivery barriers of tumor accumulation, intratumoral penetration, and cellular uptake and synergizes PEDT-starvation tumor therapy.