Engineering Seed-like Fe–Mn Nanomedicine with Ultrasmall Structure and ATP-Responsive Function for Tumor Metabolic and Redox Subversion

Since adenosine triphosphate (ATP) is an indispensable substance for tumor survival, intracellular ATP regulation has emerged as a cutting-edge antineoplastic strategy. Nevertheless, most ATP-responsive anticancer nanomedicines are established with DNA structure, coordinate polymer, and glucose oxidase as the core. Herein, in order to excavate the design possibilities of ATP-responsive nanoplatforms, an ultrasmall iron (Fe)-manganese (Mn) nanomedicine (<5 nm) was designed by a combination of bottom-up and top-down approaches, employing Fe-based reductant and Mn-based oxidant as raw materials. Due to the polyvalent Fe/Mn states, as-prepared nanomedicine was featured with ATP, hydrogen peroxide (H2O2), and nicotinamide adenine dinucleotide phosphate (NADPH) reactivities to disrupt the metabolic and redox homeostasis of breast cancer and bone metastases sites. In addition, this nanomedicine was well-suited to offer dual-mode T1/T2 magnetic resonance imaging (MRI) for tumor detection. Therefore, this work provides a novel attempt for the exploitation of ultrasmall ATP-responsive antineoplastic nanomedicine.