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

Metal oxide nanostructures with surface-defect mediated chemistry have garnered pronounced interest due to the influence of these defects in tuning the 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. The nanozymes possessed enhanced surface oxygen vacancies (VO●), strategically created under kinetically favourable synthesis conditions. Increased surface VO● promoted 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. Unlike 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.