A multi-enzyme mimetic nanozyme sensitizes esophageal cancer to CDK4/6 inhibition via oxidative stress

Esophageal squamous cell carcinoma (ESCC) exhibits frequent cell cycle pathway alterations, particularly hyperactivation of the Cyclin D1/Cyclin-dependent kinase 4 and 6 (CDK4/6) axis, but clinical trials of CDK4/6 inhibitor Palbociclib in ESCC have not shown evidence of curative effect. In this work, we rationally engineered a Pt nanoparticle-decorated monolayer CoAl layered double hydroxide nanosheet to sensitize Palbociclib and achieve synergistic antitumor efficacy in ESCC model. The nanosheet exhibits multienzyme-mimicking activities, including glutathione oxidase, catalase, oxidase, and peroxidase-like, which generate substantial reactive oxygen species (ROS) together with intracellular glutathione depletion. The elevated ROS levels effectively attenuate palbociclib-triggered adaptive responses, including compensatory activation of MAPK, PI3K-AKT-mTOR signaling pathways and the upregulation of glutathione peroxidase 4, thereby enhancing tumor suppression. Our work highlights nanozyme-mediated oxidative stress amplification as a promising strategy for sensitizing molecular-targeted therapies.