Atomic iron-engineered dual-modal nanozyme enhances tumor-targeted chemodynamic/photothermal synergistic therapy

To address monotherapy limitations in oncology, synergistic strategies are urgently needed to circumvent drug resistance and achieve favorable therapeutic outcomes. The development of new nanoformulations has emerged as one of the most promising approaches to resolve these challenges. In this study, we engineered an iRGD peptide-functionalized Fe single-atom nanozyme (FeSAN@iRGD) that integrates dual therapeutic modalities. The FeSAN@iRGD demonstrates exceptional peroxidase-like catalytic activity and achieves a remarkable 29.5% photothermal conversion efficiency under 808 nm laser irradiation, enabling effective synergistic chemodynamic therapy (CDT) and photothermal therapy (PTT). Density functional theory calculations reveal that the atomically dispersed Fe-N₄ active sites facilitate efficient catalytic conversion of endogenous H₂O₂ into highly cytotoxic hydroxyl radicals in tumor microenvironment. The surface-conjugated iRGD peptide significantly enhances tumor-targeted accumulation. Both in vitro and in vivo evaluations confirm that the combined CDT/PTT approach synergistically enhances tumor cell apoptosis and suppresses tumor growth. Proteomic analysis comprehensively revealed reactive oxygen species (ROS)-mediated pathways including response to ROS, apoptosis, metabolic reprogramming, and cell cycle. This multifunctional nanozyme provides a promising paradigm for overcoming the therapeutic limitations of conventional cancer treatments through rational integration of catalytic nanomedicine and tumor-targeting strategies.