CD44 and αV-integrins dual-targeting bimetallic nanozymes for lung adenocarcinoma therapy via NIR-enhanced ferroptosis/apoptosis

  • Biomaterials. 2025 Dec:323:123407. doi: 10.1016/j.biomaterials.2025.123407.
Jingchuan He  1 ,  Tingting Li  2 ,  Xiaoqin Pan  3 ,  Zhihua Deng  4 ,  Jifu Huang  3 ,  Xiaocheng Mo  5 ,  Xiaoju Shen  5 ,  Xiumei Qin  3 ,  Xingye Yang  6 ,  Ming Gao  7 ,  Jie Yang  8
Affiliations
  • 1. Department of Pharmacology, School of Pharmacy, Guangxi Medical University, Nanning, 530021, China; Department of Pharmacy, Guangxi Medical University Cancer Hospital, Nanning, 530021, China.
  • 2. 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.
  • 3. Department of Pharmacology, School of Pharmacy, Guangxi Medical University, Nanning, 530021, China.
  • 4. Department of Pharmacology, School of Pharmacy, Guangxi Medical University, Nanning, 530021, China; Department of Gastrointestinal Medicine, Affiliated Hospital of YouJiang Medical University for Nationalities, Baise, 533000, China.
  • 5. Department of Pharmacology, School of Pharmacy, Guangxi Medical University, Nanning, 530021, China; Department of Pharmacy, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China.
  • 6. Department of Pharmaceutics, School of Pharmacy, Guangxi Medical University, Nanning, 530021, China.
  • 7. Life Sciences Institute, Guangxi Medical University, Nanning, 530021, China. Electronic address: [email protected].
  • 8. Department of Pharmacology, School of Pharmacy, Guangxi Medical University, Nanning, 530021, China; Guangxi Key Laboratory of Drug Basic Research for Prevention and Treatment of Geriatric Diseases, School of Pharmacy, Guangxi Medical University, Nanning, 530021, China; The Laboratory of Toxicology of Traditional Chinese Medicine, Level III Laboratory of National Administration of Traditional Chinese Medicine, School of Pharmacy, Guangxi Medical University, Nanning, 530021, China. Electronic address: [email protected].
PMID: 40403445 DOI: 10.1016/j.biomaterials.2025.123407
Abstract

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.

Keywords
CD44 and αV-integrin receptors; Dual-targeting bimetallic nanozymes; Ferroptosis and apoptosis; Lung cancer therapy; NIR.
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