An AND Logic Gate for Magnetic‐Resonance‐Imaging‐Guided Ferroptosis Therapy of Tumors

Abstract To improve the magnetic resonance imaging (MRI) efficiency and ferroptosis therapy efficacy of exceedingly small magnetic iron oxide nanoparticles (IO, <5 nm) for tumors via enhancing the sensitivity of tumor microenvironment (TME) responsiveness, inspired by molecular logic gates, a self‐assembled IO with an AND logic gate function is designed and constructed. Typically, cystamine (CA) is conjugated onto the end of poly(2‐methylthio‐ethanol methacrylate) (PMEMA) to generate PMEMA‐CA. The PMEMA‐CA is grafted onto the surface of brequinar (BQR)‐loaded IO to form IO‐BQR@PMEMA. The self‐assembled IO‐BQR@PMEMA (SA‐IO‐BQR@PMEMA) is obtained due to the hydrophobicity of PMEMA. The carbon–sulfur single bond of PMEMA‐CA can be oxidized by reactive oxygen species (ROS) in the TME to a thio–oxygen double bond, resulting in the conversion from being hydrophobic to hydrophilic. The disulfide bond of PMEMA‐CA can be broken by the glutathione (GSH) in the TME, leading to the shedding of PMEMA from the IO surface. Under the dual actions of ROS and GSH in TME (i.e., AND logic gate), SA‐IO‐BQR@PMEMA can be disassembled to release IO, Fe^2+/3+, and BQR. In vitro and in vivo results demonstrate the AND logic gate function and mechanism, the high T₁ MRI performance and exceptional ferroptosis therapy efficacy for tumors, and the excellent biosafety of SA‐IO‐BQR@PMEMA.