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 (H 2 O 2 ), 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 T 1 /T 2 magnetic resonance imaging (MRI) for tumor detection. Therefore, this work provides a novel attempt for the exploitation of ultrasmall ATP-responsive antineoplastic nanomedicine.