癌细胞和正常细胞之间活性氧（ROS）利用的差异构成了癌症精准治疗的关键节点，在靶向治疗领域描绘了一条值得注意的轨迹。这一现象在纳米药物精准治疗领域尤为突出。尽管在使用纳米颗粒破坏 ROS 进行癌症治疗方面取得了长足的进步，但当前的策略仍在应对与功效和特异性相关的挑战。主要障碍之一在于细胞内谷胱甘肽 (GSH) 水平升高。目前，减少细胞内 GSH 的主要方法包括抑制其合成或促进 GSH 外流。然而，由于缺乏能够直接有效地清除 GSH 的策略，仍然存在明显的差距。我们最初阐明了冬凌草甲素的化学机制，冬凌草甲素是一种小药理制剂，被证明通过与谷胱甘肽的共价相互作用来扰乱活性氧。随后，我们采用马来酰亚胺脂质体（以其破坏 ROS 递送系统的能力而闻名）来改善药物的水溶性和药代动力学，从而增强其 ROS 破坏功效。为了进一步完善急性髓系白血病 (AML) 的靶向，我们利用马来酰亚胺和硫醇反应机制，促进 Toll 样受体 2 (TLR2) 肽通过马来酰亚胺与脂质体表面偶联。这种策略方法为精确去除 GSH 提供了一种新方法，其增强努力旨在增强药物对 AML 靶点影响的精度和功效。我们证明，这种肽-脂质体-小分子机制以 AML 为目标，从而诱导通过三种不同的机制在体外和体内细胞凋亡：（I）冬凌草甲素作为迈克尔受体分子，通过共价键抑制 GSH 功能，引发氧化应激的初始失衡。 (II) 作为与冬凌草甲素的补充，马来酰亚胺进一步诱导 GSH 耗竭，加剧氧化还原失衡。 (III) 肽靶向 TLR2，增强 AML 细胞内冬凌草甲素的定向性和富集性。合理设计的纳米复合物提供了 ROS 药物增强和靶向递送平台，通过破坏氧化还原平衡为 AML 治疗提供了潜在的解决方案。© 2024。作者（ s）。

Discrepancies in the utilization of reactive oxygen species (ROS) between cancer cells and their normal counterparts constitute a pivotal juncture for the precise treatment of cancer, delineating a noteworthy trajectory in the field of targeted therapies. This phenomenon is particularly conspicuous in the domain of nano-drug precision treatment. Despite substantial strides in employing nanoparticles to disrupt ROS for cancer therapy, current strategies continue to grapple with challenges pertaining to efficacy and specificity. One of the primary hurdles lies in the elevated levels of intracellular glutathione (GSH). Presently, predominant methods to mitigate intracellular GSH involve inhibiting its synthesis or promoting GSH efflux. However, a conspicuous gap remains in the absence of a strategy capable of directly and efficiently clearing GSH.We initially elucidated the chemical mechanism underpinning oridonin, a diminutive pharmacological agent demonstrated to perturb reactive oxygen species, through its covalent interaction with glutathione. Subsequently, we employed the incorporation of maleimide-liposomes, renowned for their capacity to disrupt the ROS delivery system, to ameliorate the drug's water solubility and pharmacokinetics, thereby enhancing its ROS-disruptive efficacy. In a pursuit to further refine the targeting for acute myeloid leukemia (AML), we harnessed the maleic imide and thiol reaction mechanism, facilitating the coupling of Toll-like receptor 2 (TLR2) peptides to the liposomes' surface via maleic imide. This strategic approach offers a novel method for the precise removal of GSH, and its enhancement endeavors are directed towards fortifying the precision and efficacy of the drug's impact on AML targets.We demonstrated that this peptide-liposome-small molecule machinery targets AML and consequently induces cell apoptosis both in vitro and in vivo through three disparate mechanisms: (I) Oridonin, as a Michael acceptor molecule, inhibits GSH function through covalent bonding, triggering an initial imbalance of oxidative stress. (II) Maleimide further induces GSH exhaustion, aggravating redox imbalance as a complementary augment with oridonin. (III) Peptide targets TLR2, enhances the directivity and enrichment of oridonin within AML cells.The rationally designed nanocomplex provides a ROS drug enhancement and targeted delivery platform, representing a potential solution by disrupting redox balance for AML therapy.© 2024. The Author(s).