为了通过增强肿瘤微环境(TME)的敏感性，改善超小型磁性氧化铁纳米颗粒(IO, < 5 nm) 在磁共振成像(MRI)效率和铁死亡疗法疗效方面的应用，受分子逻辑门的启示，我们设计并构建了一个具有AND逻辑门功能的自组装IO。通常情况下，我们将半胱氨酸(CA) 接枝到聚(2-甲基硫乙醇甲基丙烯酸酯)(PMEMA) 端上，生成PMEMA-CA。然后将PMEMA-CA嫁接到带有替构焦甘革碱(BQR) 的IO表面，形成IO-BQR@PMEMA。由于PMEMA的疏水性，自组装IO-BQR@PMEMA (SA-IO-BQR@PMEMA) 得以形成。PMEMA-CA的碳硫单键可以被肿瘤微环境中的活性氧(ROS) 氧化为硫氧双键，从而从疏水性转变为亲水性。PMEMA-CA的二硫键可以被肿瘤微环境中的谷胱甘肽(GSH) 断裂，导致PMEMA从IO表面脱落。在肿瘤微环境中，通过ROS和GSH的双重作用（即AND逻辑门），SA-IO-BQR@PMEMA可以解离释放出IO，Fe2+/3+和BQR。体内外实验结果证明了AND逻辑门的功能和机制、高T1 MRI性能、卓越的肿瘤铁死亡疗法疗效以及SA-IO-BQR@PMEMA的出色生物安全性。本文受版权保护，版权所有。

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, we designed and constructed a self-assembled IO with a AND logic gate function. Typically, cystamine (CA) was conjugated onto the end of poly(2-methylthio-ethanol methacrylate) (PMEMA) to generate PMEMA-CA. The PMEMA-CA was grafted onto the surface of brequinar (BQR)-loaded IO to form IO-BQR@PMEMA. The self-assembled IO-BQR@PMEMA (SA-IO-BQR@PMEMA) was obtained due to the hydrophobicity of PMEMA. The carbon-sulfur single bond of PMEMA-CA can be oxidized by the reactive oxygen species (ROS) in TME to 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 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, Fe2+/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. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.