Framework nucleic acid-based nanoparticles enhance temozolomide sensitivity in glioblastoma

Yufei Lan; Xiaodie Li; Boyang Liu; Jiankun Lu; Boming Zuo; Yue Wang; Shuting Cao; Xin Fu; Qu Yue; Xin Luo; Xiangyang Zhong; Yaoyuan Dong; Zhao Wang; Tao Yang; Xinyun Xie; Tianci Zeng; Manqing Zhang; Yuankai Wang; Yixiong Shen; Huaqin Zuo; Yan Zhao; Chao Zhang; Hongbo Guo

doi:10.1016/j.drup.2024.101122

Framework nucleic acid-based nanoparticles enhance temozolomide sensitivity in glioblastoma

Drug Resist Updat. 2024 Sep:76:101122. doi: 10.1016/j.drup.2024.101122. Epub 2024 Jul 27.

Authors

Yufei Lan¹, Xiaodie Li¹, Boyang Liu², Jiankun Lu¹, Boming Zuo¹, Yue Wang³, Shuting Cao⁴, Xin Fu¹, Qu Yue¹, Xin Luo¹, Xiangyang Zhong¹, Yaoyuan Dong¹, Zhao Wang¹, Tao Yang¹, Xinyun Xie¹, Tianci Zeng¹, Manqing Zhang¹, Yuankai Wang¹, Yixiong Shen¹, Huaqin Zuo⁵, Yan Zhao⁶, Chao Zhang⁷, Hongbo Guo⁸

Affiliations

¹ Department of Neurosurgery, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
² Department of Neurosurgery, Department of Neuro-oncological Surgery, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
³ Division of Physical Biology, CAS Key Laboratory of Interfacial Physics and Technology, Shanghai Institute of Applied Physics, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 201800, China.
⁴ Xiangfu Laboratory, Jiashan 314102, China.
⁵ Department of Hematology, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, Jiangsu 225001, China. Electronic address: [email protected].
⁶ Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen 518132, China. Electronic address: [email protected].
⁷ Department of Neurosurgery, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China. Electronic address: [email protected].
⁸ Department of Neurosurgery, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China. Electronic address: [email protected].

PMID: 39079407
DOI: 10.1016/j.drup.2024.101122

Abstract

O⁶-methylguanine DNA methyltransferase (MGMT) is a crucial determinant of temozolomide (TMZ) sensitivity in patients with glioblastoma (GBM). The therapeutic potential of small interfering RNA (siRNA) targeting MGMT to enhance TMZ sensitivity has been hampered by serum nuclease degradation, off-target effects, poor accumulation at tumor sites, and low circulation in blood stream. In this study, we developed a framework nucleic acid-based nanoparticles (FNN), which is constructed from a six-helix DNA bundle, to encapsulate and protect siMGMT for improving TMZ sensitivity in GBM treatment. For better blood-brain barrier (BBB) penetration and GBM targeting, we conjugated Angiopep-2 (ANG) targeting modules to each end of the FNN. Nucleolin (NCL)-responsive locks were engineered along the sides of the six-helix DNA bundle, which safeguard siMGMT before tumor entry. Upon interaction with tumor-overexpressed NCL, these locks unlock, exposing siMGMT, this allows for effective suppression of MGMT, resulting in a significant improvement of TMZ therapeutic efficacy in GBM. This innovative strategy has the potential to transform the current treatment landscape for GBM.

Keywords: DNA framework; DNA nanotechnology; Glioblastoma; SiRNA; Temozolomide sensitivity.

MeSH terms

Animals
Antineoplastic Agents, Alkylating* / pharmacology
Antineoplastic Agents, Alkylating* / therapeutic use
Blood-Brain Barrier* / drug effects
Blood-Brain Barrier* / metabolism
Brain Neoplasms* / drug therapy
Brain Neoplasms* / genetics
Brain Neoplasms* / pathology
Cell Line, Tumor
DNA Modification Methylases / metabolism
DNA Repair Enzymes / genetics
DNA Repair Enzymes / metabolism
Drug Resistance, Neoplasm / drug effects
Glioblastoma* / drug therapy
Glioblastoma* / pathology
Humans
Nanoparticles* / chemistry
Nucleic Acids
Nucleolin
Peptides
Phosphoproteins / metabolism
RNA, Small Interfering / administration & dosage
RNA-Binding Proteins / metabolism
Temozolomide* / administration & dosage
Temozolomide* / pharmacology
Temozolomide* / therapeutic use
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / metabolism

Substances

Temozolomide
Antineoplastic Agents, Alkylating
Angiopep-2
RNA-Binding Proteins
DNA Repair Enzymes
DNA Modification Methylases
Nucleolin
Phosphoproteins
Tumor Suppressor Proteins
RNA, Small Interfering
MGMT protein, human
Nucleic Acids
Peptides