He Jingchuan, Li Tingting, Pan Xiaoqin, Deng Zhihua, Huang Jifu, Mo Xiaocheng, Shen Xiaoju, Qin Xiumei, Yang Xingye, Gao Ming, Yang Jie
Department of Pharmacology, School of Pharmacy, Guangxi Medical University, Nanning, 530021, China; Department of Pharmacy, Guangxi Medical University Cancer Hospital, Nanning, 530021, China.
Department of Pharmacology, School of Pharmacy, Guangxi Medical University, Nanning, 530021, China; Department of Pharmacy, The Second Affiliated Hospital of North Sichuan Medical College, Nanchong, 637100, China.
Biomaterials. 2025 Dec;323:123407. doi: 10.1016/j.biomaterials.2025.123407. Epub 2025 May 13.
Combination therapy is a promising strategy for lung adenocarcinoma (LUAD), due to the advantages of overcoming drug resistance, side effects, and tumor heterogeneity. Herein, we report a novel dual-targeting bimetallic nanozyme (MH-iRGD) consisting of nanosized manganese ferrite (MF) after encapsulating with dopamine and methacrylic anhydride to modify hyaluronic acid, followed by integrin receptor targeting peptide (HS-PEG3400-iRGD) modification for LUAD targeted therapy. Our study confirmed that MH-iRGD combined with near-infrared irradiation (NIR) possessed dramatic photothermal effects and reactive oxygen species (ROS) production and GSH depletion abilities. Importantly, MH-iRGD possessed dual-targeting capacities for LUAD cells overexpressed CD44 and αV-integrin receptors owing to hyaluronic acid coating and iRGD modification. Inhibitors of CD44 and integrins could impair the uptake of MH-iRGD in LUAD cells. Moreover, MH-iRGD + NIR displayed excellent anti-LUAD effects as a result of the production of intracellular ROS, consumption of glutathione (GSH) and mitochondrial dysfunction. Mechanistically, NIR robustly strengthened MH-iRGD-induced ferroptosis and apoptosis by down-regulating SLC7A11, GPX4, Bcl-2 levels while up-regulating Bax level. Specifically, ferroptosis and apoptosis were increased while the LUAD progression was inhibited after intravenous injection of MH-iRGD + NIR in xenograft mouse models. Taken together, our results indicate that MH-iRGD + NIR serves as a promising targeted therapy for LUAD, which broadens the applications of highly active dual-targeting bimetallic nanozymes.
联合治疗是一种有前景的肺腺癌（LUAD）治疗策略，因为它具有克服耐药性、副作用和肿瘤异质性的优势。在此，我们报道了一种新型双靶向双金属纳米酶（MH-iRGD），它由纳米尺寸的锰铁氧体（MF）组成，先用多巴胺和甲基丙烯酸酐包裹以修饰透明质酸，然后进行整合素受体靶向肽（HS-PEG3400-iRGD）修饰用于LUAD的靶向治疗。我们的研究证实，MH-iRGD与近红外照射（NIR）联合具有显著的光热效应、活性氧（ROS）生成能力和谷胱甘肽（GSH）消耗能力。重要的是，由于透明质酸包被和iRGD修饰，MH-iRGD对过表达CD44和αV整合素受体的LUAD细胞具有双靶向能力。CD44和整合素的抑制剂可削弱LUAD细胞对MH-iRGD的摄取。此外，由于细胞内ROS的产生、谷胱甘肽（GSH）的消耗和线粒体功能障碍，MH-iRGD + NIR显示出优异的抗LUAD效果。机制上，NIR通过下调SLC7A11、GPX4、Bcl-2水平，同时上调Bax水平，有力地增强了MH-iRGD诱导的铁死亡和凋亡。具体而言，在异种移植小鼠模型中静脉注射MH-iRGD + NIR后，铁死亡和凋亡增加，而LUAD进展受到抑制。综上所述，我们的结果表明，MH-iRGD + NIR是一种有前景的LUAD靶向治疗方法，拓宽了高活性双靶向双金属纳米酶的应用。
