Developing intrinsically mitochondria-targetable nanosystems for subcellular structure-oriented precise cancer therapy is highly desirable. Here, we conjugate the cluster determinant 44 (CD44)-targetable hyaluronic acid (HA) with cholesterol-poly(ethylene glycol)_2k-NH₂ and mitochondria-acting IR825-NH₂ (a cyanine dye) to construct a self-assembled nanostructure (abbreviated as HA-IR825-Chol) for photothermal therapy. The HA-IR825-Chol exhibits improved photostability and desirable photothermal properties, and can rapidly and substantially enter CD44-over-expressed cancer cells and selectively accumulate in the mitochondria of the cells. Upon near-infrared laser irradiation, it can induce severe mitochondrial damage, which causes cytochrome c release and triggers cell apoptosis. Furthermore, we demonstrate the feasibility of loading the chemother-apeutics 10-hydroxycamptothecin (HCPT) into the hydrophobic cores of HA-IR825-Chol NPs for combined chemo-photothermal therapy. HCPT encapsulated within HA-IR825-Chol achieves significantly increased cellular uptake and simultaneous mitochondrial and nuclear localization, leading to the release of cytochrome c from mitochondria and upregulation of cleaved caspase-3, both of which contribute to the cell apop-tosis/death. In vivo experiments reveal the excellent tumor-targeting ability of HA-IR825-Chol/HCPT, ensuring the efficient tumor eradication by the chemo-photothermal therapy. This work exemplifies the development of an intrinsically mitochon-dria-targetable nanocarrier for precise subcellular structure-localized drug delivery, and the Choi-mediated rapid and massive endocytosis of the nanoagents may represent a robust strategy for enhancing the efficacies of nanomedicines.

非常需要开发固有的线粒体可靶向纳米系统用于面向亚细胞结构的精确癌症治疗。在这里，我们将簇决定簇44（CD44）-可靶向的透明质酸（HA）与胆固醇-聚（乙二醇）_2k -NH ₂和线粒体作用的IR825-NH _2共轭。（花青染料）以构建用于光热疗法的自组装纳米结构（缩写为HA-IR825-Chol）。HA-IR825-Chol表现出改善的光稳定性和所需的光热特性，并且可以迅速且基本上进入过度表达CD44的癌细胞并选择性地积聚在细胞的线粒体中。在近红外激光照射下，它可以诱导严重的线粒体损伤，从而导致细胞色素c释放并触发细胞凋亡。此外，我们证明了将化疗药10-羟基喜树碱（HCPT）加载到HA-IR825-Chol NPs的疏水核中进行化学光热疗法的可行性。封装在HA-IR825-Chol中的HCPT可以显着提高细胞摄取，同时实现线粒体和核定位，体内实验显示，HA-IR825-Chol / HCPT具有出色的肿瘤靶向能力，可确保通过化学光热疗法有效根除肿瘤。这项工作举例说明了一种固有的线粒体-dria-可靶向纳米载体的开发，用于精确的亚细胞结构定位的药物递送，而Choi介导的纳米剂的快速大量内吞作用可能代表了一种增强纳米药物功效的有效策略。