Drug-Free Multi-Modal Non-invasive Cancer Therapy via Oxygen Vacancy Engineered Biomimetic Cerium Oxide Nanozymes

Contemporary challenges in chemotherapy for triple negative breast cancer (TNBC) are inadequate specificity towards malignant cells, constraints imposed by dose-related toxicities, and side effects on normal cells. To address these bottlenecks, our study introduces, a drug-free “trojan horse-like” folate functionalized, L-arginine-coated ceria (FA-L-arg-CeO2) nanoplatform for treating metastatic TNBC. We show that this engineered nanozyme exhibiting enhanced surface oxygen vacancies (VO●) facilitated band structure reconstruction and amplified the photothermal/photodynamic therapeutic (PTT/PDT) efficacy under single laser irradiation (808 nm) through reactive oxygen species (ROS) production, thereby outperforming the surface defect-free commercial nano-CeO2 in rapid tumour ablation (86% in 48 h). This low-cost targeted therapy facilitated substantial folate receptor-mediated endocytosis and accumulation of the biostable nanozymes in MDA-MB-231 cells (84% in 48 h). These drug-free VO●-rich FA-L-arg-CeO2 nanostructures were found to exhibit distinctive pH-active multi-enzyme mimicking characteristics, imparting exceptional therapeutic potential and effectively inhibited cell metastasis (62% within 12 h). Mechanistically, we observed that electrons generated at the VO●-rich surface during laser irradiation modulate the pH-responsive intracellular redox balance, synergistically killing the MDA-MB-231 cancer cells and safeguarding the benign L929 cells. Unlike drug-loaded CeO2-based nanoplatforms, the nanozymes protected the healthy cells from radiation damage through photo-triggered-ROS scavenging by mimicking catalase. This novel, drug-free nanozyme-based therapy leads the way for smart, bio-inspired multi-modal cancer treatments, ensuring enhanced efficacy and bio-safety.