A novel tetrahedral framework nucleic acid-derived chemodynamic therapy agent for effective glioblastoma treatment

Abstract

Chemodynamic therapy (CDT) has garnered significant attention for treating diverse malignant tumours due to its minimally invasive nature, reduced damage to healthy tissues, and potential mitigation of side effects. However, its application in glioblastoma (GBM) is hindered by the diminished capacity of CDT agents to traverse the blood–brain barrier (BBB), inadequate tumour targeting efficiency, and restricted availability of H₂O₂ within the tumour microenvironment (TME). To address these challenges, we devised a novel CDT agent (Fe@tFNAs-ANG-3AT) based on a tetrahedral framework nucleic acids (tFNAs). Fe@tFNAs-ANG-3AT was constructed by anchoring iron ions (Fe³⁺) onto the dual appendages-modified tFNAs. Specifically, one appendage, Angiopep-2 (ANG, a penetrating peptide), facilitates Fe@tFNAs-ANG-3AT penetration across the BBB and selective targeting of tumour cells. Simultaneously, the second appendage, 3-Amino-1,2,4-triazole (3AT, a H₂O₂ enzyme inhibitor), augments the H₂O₂ levels required for effective CDT treatment. Upon tumour cell internalization, the loaded Fe³⁺ in Fe@tFNAs-ANG-3AT is reduced to Fe²⁺ by the overexpressed glutathione (GSH) in the TME, catalysing the generation of cytotoxic hydroxyl radicals (•OH) and inducing tumour cell death via elevated oxidative stress levels within tumour cells. It is anticipated that Fe@tFNAs-ANG-3AT holds promise as a transformative treatment strategy for GBM.

References

[1] van den BentMJ, GeurtsM, FrenchPJ, et al. Primary brain tumours in adults. Lancet. 2023;402(10412):1564-1579.

[2] PeshoffMM, GuptaP, OberaiS, et al. Triggering receptor expressed on myeloid cells 2 (TREM2) regulates phagocytosis in glioblastoma. Neuro-Oncology. 2024;26:826-839.

[3] AlexanderBM, Cloughesy TF. Adult Glioblastoma. J Clin Oncol. 2017;35(21):2402-2409.

[4] FliesCM, Friedrich M, LohmannP, et al. Treatment-associated imaging changes in newly diagnosed MGMT promoter-methylated glioblastoma undergoing chemoradiation with or without cilengitide. Neuro-Oncology. 2024;26:902-910.

[5] LouisDN, PerryA, WesselingP, et al. The 2021 WHO classification of tumors of the central nervous system: a summary. Neuro-Oncology. 2021;23:1231-1251.

[6] KumthekarP, Rademaker A, KoC, et al. A phase 0 first-in-human study using NU-0129: a gold base spherical nucleic acid (SNA) nanoconjugate targeting BCL2L12 in recurrent glioblastoma patients. J Clin Oncol. 2019;37(15):3012.

[7] GuptaS, SheikhH, SchneiderC, Zhang X, PadmanabhanA, AliA. HER-2/neu expression in glioblastoma multiforme (GBM). J Clin Oncol. 2009;27(15):e13035.

[8] WuY, SongYQ, WangRZ, Wang T. Molecular mechanisms of tumor resistance to radiotherapy. Mol Cancer. 2023;22(1):96.

[9] JiangN, XieBW, XiaoWW, et al. Fatty acid oxidation fuels glioblastoma radioresistance with CD47-mediated immune evasion. Nat Commun. 2022;13(1):1511.

[10] BegagićE, Pugonja R, BečulićH, et al. Molecular targeted therapies in glioblastoma multiforme: a systematic overview of global trends and findings. Brain Sci. 2023;13(11):1602.

[11] ZhangHL, ChenY, HuaW, et al. Heterostructures with built-in electric fields for long-lasting chemodynamic therapy. Angew Chem Int Ed Engl. 2023;62(15):e202300356.

[12] ZhaoPR, LiHY, BuWB. A forward vision for chemodynamic therapy: issues and opportunities. Angew Chem Int Ed Engl. 2023;62(7):e202210415.

[13] ZhouYF, FanSY, FengLL, Huang X, ChenX. Manipulating intratumoral fenton chemistry for enhanced chemodynamic and chemodynamic-synergized multimodal therapy. Adv Mater. 2021;33(48):e2104223.

[14] BaoYW, HuaXW, ZengJ, Wu FG. Bacterial template synthesis of multifunctional nanospindles for glutathione detection and enhanced cancer-specific chemo-chemodynamic therapy. Research. 2020;2020:9301215.

[15] ZhuJF, HeG, ChenPH, et al. Terpyridine-grafted nitrogen-terminal endowing cyanine with metal-ion-regulated photophysical properties for cancer theranostics. Research. 2023;6:0061.

[16] GaoYW, LiY, XuZW, YuS, LiuJ, SunH. Multiporphyrinic architectures: advances in structural design for photodynamic therapy. Aggregate. 2023;5(1):e420.

[17] LiJH, ZhouHJ, LiuC, et al. Biomembrane-inspired design of medical micro/nanorobots: from cytomembrane stealth cloaks to cellularized Trojan horses. Aggregate. 2023;4(5):e359.

[18] BaiJ, JiaXD, ZhenWY, Cheng W, JiangX. A facile ion-doping strategy to regulate tumor microenvironments for enhanced multimodal tumor theranostics. J Am Chem Soc. 2018;140(1):106-109.

[19] XuJT, ShiRP, ChenGY, et al. All-in-one theranostic nanomedicine with ultrabright second near-infrared emission for tumor-modulated bioimaging and chemodynamic/photodynamic therapy. ACS Nano. 2020;14(8):9613-9625.

[20] YanN, LinL, XuCN, et al. A GSH-gated DNA nanodevice for tumor-specific signal amplification of microRNA and MR imaging-guided theranostics. Small. 2019;15(41):e1903016.

[21] AkdoganCZS, Çetin EA, OnurMA, et al. In vitro synergistic photodynamic, photothermal, chemodynamic, and starvation therapy performance of chlorin e6 immobilized, polydopamine-coated hollow, porous ceria-based, hypoxia-tolerant nanozymes carrying a cascade system. ACS Appl Bio Mater. 2024;7(5):2781-2793.

[22] AmodioA, ZhaoB, PorchettaA, et al. Rational design of pH-controlled DNA strand displacement. J Am Chem Soc. 2014;136(47):16469-16472.

[23] PeiH, ZuoXL, ZhuD, HuangQ, FanC. Functional DNA nanostructures for theranostic applications. Acc Chem Res. 2014;47(2):550-559.

[24] HuQQ, LiH, WangLH, Gu H, FanC. DNA nanotechnology-enabled drug delivery systems. Chem Rev. 2019;119(10):6459-6506.

[25] KihalN, NguyenPT, NazemiA, Greschner AA, GauthierMA, BourgaultS. DNA nanostructures prevent the formation of and convert toxic amyloid proteospecies into cytocompatible and biodegradable spherical complexes. Aggregate. 2024;5:e502.

[26] ZhaiT, LiQ, ShenJ, Li J, FanC. DNA nanostructure-encoded fluorescent barcodes. Aggregate. 2020;1(1):107-116.

[27] XieM, HuY, YinJ, ZhaoZ, ChenJ, Chao J. DNA nanotechnology-enabled fabrication of metal Nanomorphology. Research. 2022;2022:9840131.

[28] WirajaC, ZhuY, LioDCS, et al. Framework nucleic acids as programmable carrier for transdermal drug delivery. Nat Commun. 2019;10(1):1147.

[29] LiuXG, ZhangF, JingXX, et al. Complex silica composite nanomaterials templated with DNA origami. Nature. 2018;559(7715):593-598.

[30] LiJ, GreenAA, YanH, FanC. Engineering nucleic acid structures for programmable molecular circuitry and intracellular biocomputation. Nat Chem. 2017;9(11):1056-1067.

[31] ZhaoHP, LiMQ, LuSS, et al. The enhancement of enzyme cascading via tetrahedral DNA framework modification. Analyst. 2023;148(4):906-911.

[32] TianT, LiJ, XieC, et al. Targeted imaging of brain tumors with a framework nucleic acid probe. ACS Appl Mater Interfaces. 2018;10(4):3414-3420.

[33] CaoZC, LiuX, ZhangWQ, et al. Biomimetic macrophage membrane-camouflaged nanoparticles induce ferroptosis by promoting mitochondrial damage in glioblastoma. ACS Nano. 2023;17(23):23746-23760.

[34] LingJ, WangBB, LiXN, et al. Multifunctional iron-doped hollow mesoporous silica nanoregulator for enhanced tumor chemodynamic therapy. Part Part Syst Charact. 2023;40(9):2300054.

[35] ShaoFY, HanJY, TianZY, Wang Z, LiuS, WuY. Synergistic ROS generation and directional overloading of endogenous calcium induce mitochondrial dysfunction in living cells. Biomaterials. 2023;301:122284.

[36] IdelchikMDPS, BegleyU, BegleyTJ, et al. Mitochondrial ROS control of cancer. Semin Cancer Biol. 2017;47:57-66.

[37] LiuX, CaoZ, WangW, et al. Engineered extracellular vesicle-delivered CRISPR/Cas9 for radiotherapy sensitization of glioblastoma. ACS Nano. 2023;17(17):16432-16447.

[38] XueJ, ZhaoZ, ZhangL, et al. Neutrophil-mediated anticancer drug delivery for suppression of postoperative malignant glioma recurrence. Nat Nanotechnol. 2017;12(7):692-700.

RIGHTS & PERMISSIONS

2024 The Author(s). Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.