Rationalizing Defective Biomimetic Ceria: In Vitro Demonstration of a Potential “Trojan Horse” Nanozyme Based‐Platform Leveraging Photo‐Redox Activities for Minimally Invasive Therapy

Semiconductor nanostructures with surface defect‐mediated chemistry have garnered pronounced interest due to their exceptional photo‐induced intracellular bio‐catalytic (enzyme‐mimicking) responses. However, designing defective nanozymes with pH‐responsive multi‐bio‐catalytic functions without any dopants is challenging. Herein, oxygen‐deficient “trojan horse‐like” folate‐functionalized, L‐arginine‐coated ceria (FA‐L‐arg‐CeO2) nanozymes with synergistic multi‐enzyme‐mimicking and anti‐cancer potential are introduced. Intrinsic surface oxygen vacancies (VO●) are strategically created in the nanozymes under kinetically favorable synthesis conditions. Increased surface VO● promotes band structure reconstruction and amplified photochemical‐response efficacy under single laser irradiation (808 nm), outperforming the defect‐free commercial nano‐CeO2 in rapid anti‐tumorigenic activities. Through folate receptor‐mediated endocytosis, these biostable nanozymes localized in MDA‐MB‐231 cells (84% in 48 h) and demonstrated NIR‐accelerated enzymatic functions depending on the pH of the biological milieu. The reduced band gap energy facilitated effective electron‐hole separation, up‐regulating in vitro photo‐redox reactions that impart exceptional therapeutic potential and inhibit 62% cell metastasis within only 12 h. By perturbing intratumoural redox homeostasis, VO●‐rich FA‐L‐arg‐CeO2 nanozymes unanimously killed 86% of MDA‐MB‐231 cancer cells while preferentially shielding benign L929 cells. Transcending beyond conventional drug‐loaded or dopant‐incorporated‐CeO2 nanoplatforms, these defective multi‐modal nanozymes unravel a new avenue for developing smart, low‐cost, bio‐active agents with enhanced efficacy and bio‐safety.