Fe-O-Mo Site-Activated Nanozymes for Bienzymatic/Upconversion Synergistic Catalytic Anticancer Therapy

Single-atom nanozymes (SAzymes) hold promise for cancer therapy but suffer from low active site density and restricted intermediate adsorption/desorption capabilities. Herein, Fe/Mo dual-atom silicon-based semiconductor nanozymes (FeMo_DA), encapsulated in lanthanide-doped nanoparticles (LPs) and surface-modified with hyaluronic acid (HA) (denoted as HA/FeMo_DA-LPs), were developed for synergistic bienzymatic/upconversion-triggered catalytic therapy (ET/UCT) under second near-infrared (NIR-II)/magnetic resonance (MR) imaging guidance. Density functional theory calculations revealed that Fe/Mo dual-atom sites were bridged by Fe - O - Mo coordination, optimizing oxygen-containing intermediate adsorption/desorption, and improving dual-enzymatic activities. The peroxidase (POD)-like catalytic performance of HA/FeMo_DA-LPs showed a K_m of 11.54 mM and a V_max of 1.14 × 10^-7 M·s^-1, outperforming Fe- or Mo-single-atom coated LPs. HA modification promoted endocytosis (∼5.67-fold) and microenvironmental acidification (pH from 7.21 to 6.74), further improving ET. Under 980 nm irradiation, upconversion-triggered electrons synergized with oxidase-like activity to convert O₂ into superoxide (•O₂ ^-), while holes enabled •O₂ ^- to singlet oxygen (¹O₂) conversion, which combined with POD-like-produced hydroxyl radicals (•OH) to achieve synergistic ET/UCT. Tumor H⁺ and glutathione co-induced the specific degradation of nanozymes, resulting in tumor self-enhanced downconversion NIR-II and MR imaging. Compared with conventional SAzymes, HA/FeMo_DA-LPs exhibit superior catalytic performance and dual-modal imaging, offering a synergistic and tumor-responsive platform for cancer theranostics.