细胞铁与线粒体的适当功能密不可分，因为线粒体具有易于捐赠和接受电子的潜力。尽管前景广阔，但铁螯合抗肿瘤疗法的现有尝试往往是辅助疗法。在此，我们构思并制造了一种“铁自噬”纳米颗粒（Dp44mT@HTH），它能够通过抑制受损线粒体的自噬清除来诱导线粒体的绝对破坏，从而促进癌细胞死亡。以透明质酸（HA）为亲水外壳的Dp44mT@HTH可以特异性靶向4T1肿瘤细胞表面高表达的CD44受体。内化和溶酶体逃逸后，纳米颗粒在活性氧 (ROS) 的作用下分解，随后释放铁螯合剂 Dp44mT 和自噬抑制药物羟氯喹 (HCQ)。然后，Dp44mT 可以捕获细胞内的 Fe2，通过呼吸链紊乱引发线粒体功能障碍，而 HCQ 不仅减少 Fe2 的摄入，还会阻碍自噬体和溶酶体的融合。因此，Dp44mT@HTH 会诱导不可逆的线粒体损伤，从而产生大量的毒性堆积状态，从而诱导细胞凋亡和细胞死亡。该策略从内源性物质的角度出发，阐明了通过不可逆线粒体损伤诱导进行铁耗竭疗法用于抗癌治疗的前景。版权所有 © 2024。由 Elsevier B.V. 出版。

Cellular iron is inseparably related with the proper functionalities of mitochondria for its potential to readily donate and accept electrons. Though promising, the available endeavors of iron chelation antitumor therapies have tended to be adjuvant therapies. Herein, we conceptualized and fabricated an "iron-phagy" nanoparticle (Dp44mT@HTH) capable of inducing the absolute devastation of mitochondria via inhibiting the autophagy-removal of impaired ones for promoting cancer cell death. The Dp44mT@HTH with hyaluronic acid (HA) as hydrophilic shell can specifically target the highly expressed CD44 receptors on the surface of 4 T1 tumor cells. After internalization and lysosomal escape, the nanoparticle disassembles in response to the reactive oxygen species (ROS), subsequently releasing the iron chelator Dp44mT and autophagy-inhibitory drug hydroxychloroquine (HCQ). Dp44mT can then seize cellular Fe2+ to trigger mitochondrial dysfunction via respiratory chain disturbance, while HCQ not only lessens Fe2+ intake, but also impedes fusions of autophagosomes and lysosomes. Consequentially, Dp44mT@HTH induces irreversible mitochondrial impairments, in this respect creating a substantial toxic stack state that induces apoptosis and cell death. Initiating from the perspective of endogenous substances, this strategy illuminates the promise of iron depletion therapy via irreversible mitochondrial damage induction for anticancer treatment.Copyright © 2024. Published by Elsevier B.V.