Engineered Au@CeO₂ Hybrid Nanoparticles With Microenvironment Dependent Self-Adjustability for Integration of...

Although nanoparticle-based photothermal therapy (PTT) and chemodynamic therapy (CDT) hold great promise for tumor treatment, their clinical translation remains limited by off-target tissue damage and therapy-induced peritumoral inflammation. To address these challenges, we engineered microenvironment-adaptive Au@CeO₂ hybrid nanoparticles (ACEF) with self-adjustable structural and catalytic behaviors for integrating tumor-specific PTT/CDT with inflammation prevention. In tumor regions, FA-mediated accumulation and intracellular esterase/Ca²⁺ activation promote ACEF aggregation, thereby enhancing near-infrared (NIR)-responsive photothermal conversion and reactive oxygen species (ROS)-generating catalytic activity for localized tumor inhibition. In contrast, in surrounding normal tissues, dispersed ACEF predominantly exhibits ROS-scavenging behavior through Ce-based redox regulation, helping reduce excessive oxidative stress and inflammatory responses. This spatially adaptive behavior enables ACEF to exert therapeutic ROS/heat generation mainly in tumor-associated environments while maintaining antioxidant protection under physiological conditions. In vitro and in vivo results demonstrated that ACEF effectively suppressed primary tumor growth and lung metastasis, reduced abnormal oxidative/inflammatory responses in non-tumor tissues, and showed no obvious systemic toxicity under the tested conditions. This work provides a microenvironment-dependent self-adjustable strategy for integrating tumor-specific photothermal-chemodynamic therapy with inflammation prevention.