Oxygen‐Supplying Piezocatalytic Therapy of Hypoxic Tumors by Intratumoral Delivery of pH‐Responsive Multicompartmental Carriers with Sequential Drug Release Capability

Abstract Piezocatalytic cancer therapy, in which piezoelectric nanomaterials generate reactive oxygen species (ROS) via piezocatalytic redox reactions under mechanical stress, has emerged as an effective strategy for cancer treatment. However, the inherent hypoxia in tumor microenvironments enormously restricts its efficacy. To address this issue, acid‐degradable Janus‐type multicompartmental carriers able to separately encapsulate piezocatalytic gold nanoparticle‐coated poly(ethylene glycol)‐modified zinc oxide nanorods (Au@P‐ZnO NRs) and O₂‐generating catalase (CAT) are fabricated in this study using stop‐flow lithography (SFL). The CAT and Au@P‐ZnO NRs are sequentially released by modulating the composition ratios of acid‐cleavable monomers in the precursor solution during the SFL. The sequential release by the Janus carriers significantly increased the intracellular ROS levels under hypoxia conditions upon ultrasound irradiation owing to the O₂ supplied by the CAT. An in vivo study showed that a single intratumoral injection of Janus particles encapsulating the CAT and Au@P‐ZnO NRs efficiently alleviated tumor hypoxia and substantially suppressed tumor growth. This study demonstrates that pH‐responsive, O₂‐generating, and piezocatalytic Janus carriers have high potential for piezocatalytic therapy of hypoxic tumors and offers insights into using pH‐responsive Janus carriers for efficient hypoxia‐relieving piezocatalytic cancer therapy via the cascade of oxygenation and ROS generation.