Metal-Coordinated Histidine-Functionalized Redox-Responsive Polyethyleneimine as a Smart Gene Delivery Vector

Makkieh Jahanpeimay Sabet; Akbar Hasanzadeh; Amirhossein Vahabi; Elaheh Sadat Hosseini; Sara Saeedi; Beheshteh Khodadadi Chegeni; Jafar Kiani; Behjat Kheiri Yeghaneh Azar; Zahra Asghari Molabashi; Mehdi Shamsara; Michael R. Hamblin; Mahdi Karimi; Abazar Roustazadeh

doi:10.1007/s12033-024-01360-x

Metal-Coordinated Histidine-Functionalized Redox-Responsive Polyethyleneimine as a Smart Gene Delivery Vector

Makkieh Jahanpeimay Sabet
, Akbar Hasanzadeh
, Amirhossein Vahabi
, Elaheh Sadat Hosseini
, Sara Saeedi
, Beheshteh Khodadadi Chegeni
, Jafar Kiani
, Behjat Kheiri Yeghaneh Azar
, Zahra Asghari Molabashi
, Mehdi Shamsara
, Michael R. Hamblin
, Mahdi Karimi
, Abazar Roustazadeh

Laser Research Centre

Iran University of Medical Sciences
National Institute for Genetic Engineering and Biotechnology Iran
Tehran University of Medical Sciences
Islamic Azad University
Jahrom University of Medical Science

Research output: Contribution to journal › Article › peer-review

4 Citations (Scopus)

Abstract

Despite significant advancements in gene delivery and CRISPR technology, several challenges remain. Chief among these are overcoming serum inhibition and achieving high transfection efficiency with minimal cytotoxicity. To address these issues, there is a need for novel vectors that exhibit lower toxicity, maintain stability in serum-rich environments, and effectively deliver plasmids of various sizes across diverse cell types. In this study, to convert common polyethylenimine (PEI_1.8k) into high-performance DNA delivery vectors, an innovative multifunctional vector was constructed based on histidine linked to PEI_1.8k by redox-responsive disulfide bonds. Apart from highly efficient transfection of both small and large plasmids into HEK 293T (Human Embryonic Kidney 293T cells) with negligible cytotoxicity, PEI_1.8k-S-S-His showed great transfection potential even at low plasmid doses (0.5 µg), as well as at serum concentrations ranging from 5 to 30% into HEK 293T cells, and achieved excellent plasmid transfection into NIH/3T3 (Mouse Embryonic Fibroblast cells), and MCF7 (Human Breast Cancer cells). Additionally, several metals were tested (Co, Cu, Cd, Ni, Zn, and Mn) to promote the plasmid packaging functionality and improve transfection efficiency. We observed that, in comparison to PEI_1.8k-S-S-His, the manganese-functionalized nanocarrier (PEI_1.8k-S-S-His-Mn) could transfect a large plasmid with equal efficiency (~ 30%) into MSCs (Mesenchymal Stem Cells). Interestingly, PEI_1.8k-S-S-His-Mn showed higher transfection efficiency with the small plasmid (~ 90%) and the large one (~ 80%) into HEK 293T cells, even better than its backbone. We propose that the presence of metal-coordinated His ligand, redox-responsive S–S bonds, and the cationic polymer can synergistically provide robust DNA binding, efficient endosomal disruption, tolerance of serum protein adsorption, and low cytotoxicity. These new vectors could be promising for gene delivery and may be therapeutically relevant.

Original language	English
Pages (from-to)	170-186
Number of pages	17
Journal	Molecular Biotechnology
Volume	68
Issue number	1
DOIs	https://doi.org/10.1007/s12033-024-01360-x
Publication status	Published - Jan 2026

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Efficient plasmid delivery
High serum tolerance
Histidine-modified polymer
Metal-coordinated histidine polymer
Redox-responsive disulfide linker

ASJC Scopus subject areas

Biotechnology
Bioengineering
Biochemistry
Applied Microbiology and Biotechnology
Molecular Biology

Access to Document

10.1007/s12033-024-01360-x

Cite this

Sabet, M. J., Hasanzadeh, A., Vahabi, A., Hosseini, E. S., Saeedi, S., Chegeni, B. K., Kiani, J., Azar, B. K. Y., Molabashi, Z. A., Shamsara, M., Hamblin, M. R., Karimi, M., & Roustazadeh, A. (2026). Metal-Coordinated Histidine-Functionalized Redox-Responsive Polyethyleneimine as a Smart Gene Delivery Vector. Molecular Biotechnology, 68(1), 170-186. https://doi.org/10.1007/s12033-024-01360-x

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title = "Metal-Coordinated Histidine-Functionalized Redox-Responsive Polyethyleneimine as a Smart Gene Delivery Vector",

abstract = "Despite significant advancements in gene delivery and CRISPR technology, several challenges remain. Chief among these are overcoming serum inhibition and achieving high transfection efficiency with minimal cytotoxicity. To address these issues, there is a need for novel vectors that exhibit lower toxicity, maintain stability in serum-rich environments, and effectively deliver plasmids of various sizes across diverse cell types. In this study, to convert common polyethylenimine (PEI1.8k) into high-performance DNA delivery vectors, an innovative multifunctional vector was constructed based on histidine linked to PEI1.8k by redox-responsive disulfide bonds. Apart from highly efficient transfection of both small and large plasmids into HEK 293T (Human Embryonic Kidney 293T cells) with negligible cytotoxicity, PEI1.8k-S-S-His showed great transfection potential even at low plasmid doses (0.5 µg), as well as at serum concentrations ranging from 5 to 30\% into HEK 293T cells, and achieved excellent plasmid transfection into NIH/3T3 (Mouse Embryonic Fibroblast cells), and MCF7 (Human Breast Cancer cells). Additionally, several metals were tested (Co, Cu, Cd, Ni, Zn, and Mn) to promote the plasmid packaging functionality and improve transfection efficiency. We observed that, in comparison to PEI1.8k-S-S-His, the manganese-functionalized nanocarrier (PEI1.8k-S-S-His-Mn) could transfect a large plasmid with equal efficiency (\textasciitilde{} 30\%) into MSCs (Mesenchymal Stem Cells). Interestingly, PEI1.8k-S-S-His-Mn showed higher transfection efficiency with the small plasmid (\textasciitilde{} 90\%) and the large one (\textasciitilde{} 80\%) into HEK 293T cells, even better than its backbone. We propose that the presence of metal-coordinated His ligand, redox-responsive S–S bonds, and the cationic polymer can synergistically provide robust DNA binding, efficient endosomal disruption, tolerance of serum protein adsorption, and low cytotoxicity. These new vectors could be promising for gene delivery and may be therapeutically relevant.",

keywords = "Efficient plasmid delivery, High serum tolerance, Histidine-modified polymer, Metal-coordinated histidine polymer, Redox-responsive disulfide linker",

author = "Sabet, \{Makkieh Jahanpeimay\} and Akbar Hasanzadeh and Amirhossein Vahabi and Hosseini, \{Elaheh Sadat\} and Sara Saeedi and Chegeni, \{Beheshteh Khodadadi\} and Jafar Kiani and Azar, \{Behjat Kheiri Yeghaneh\} and Molabashi, \{Zahra Asghari\} and Mehdi Shamsara and Hamblin, \{Michael R.\} and Mahdi Karimi and Abazar Roustazadeh",

note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2025.",

year = "2026",

month = jan,

doi = "10.1007/s12033-024-01360-x",

language = "English",

volume = "68",

pages = "170--186",

journal = "Molecular Biotechnology",

issn = "1073-6085",

publisher = "Springer",

number = "1",

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Sabet, MJ, Hasanzadeh, A, Vahabi, A, Hosseini, ES, Saeedi, S, Chegeni, BK, Kiani, J, Azar, BKY, Molabashi, ZA, Shamsara, M, Hamblin, MR, Karimi, M & Roustazadeh, A 2026, 'Metal-Coordinated Histidine-Functionalized Redox-Responsive Polyethyleneimine as a Smart Gene Delivery Vector', Molecular Biotechnology, vol. 68, no. 1, pp. 170-186. https://doi.org/10.1007/s12033-024-01360-x

TY - JOUR

T1 - Metal-Coordinated Histidine-Functionalized Redox-Responsive Polyethyleneimine as a Smart Gene Delivery Vector

AU - Sabet, Makkieh Jahanpeimay

AU - Hasanzadeh, Akbar

AU - Vahabi, Amirhossein

AU - Hosseini, Elaheh Sadat

AU - Saeedi, Sara

AU - Chegeni, Beheshteh Khodadadi

AU - Kiani, Jafar

AU - Azar, Behjat Kheiri Yeghaneh

AU - Molabashi, Zahra Asghari

AU - Shamsara, Mehdi

AU - Hamblin, Michael R.

AU - Karimi, Mahdi

AU - Roustazadeh, Abazar

N1 - Publisher Copyright: © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2025.

PY - 2026/1

Y1 - 2026/1

N2 - Despite significant advancements in gene delivery and CRISPR technology, several challenges remain. Chief among these are overcoming serum inhibition and achieving high transfection efficiency with minimal cytotoxicity. To address these issues, there is a need for novel vectors that exhibit lower toxicity, maintain stability in serum-rich environments, and effectively deliver plasmids of various sizes across diverse cell types. In this study, to convert common polyethylenimine (PEI1.8k) into high-performance DNA delivery vectors, an innovative multifunctional vector was constructed based on histidine linked to PEI1.8k by redox-responsive disulfide bonds. Apart from highly efficient transfection of both small and large plasmids into HEK 293T (Human Embryonic Kidney 293T cells) with negligible cytotoxicity, PEI1.8k-S-S-His showed great transfection potential even at low plasmid doses (0.5 µg), as well as at serum concentrations ranging from 5 to 30% into HEK 293T cells, and achieved excellent plasmid transfection into NIH/3T3 (Mouse Embryonic Fibroblast cells), and MCF7 (Human Breast Cancer cells). Additionally, several metals were tested (Co, Cu, Cd, Ni, Zn, and Mn) to promote the plasmid packaging functionality and improve transfection efficiency. We observed that, in comparison to PEI1.8k-S-S-His, the manganese-functionalized nanocarrier (PEI1.8k-S-S-His-Mn) could transfect a large plasmid with equal efficiency (~ 30%) into MSCs (Mesenchymal Stem Cells). Interestingly, PEI1.8k-S-S-His-Mn showed higher transfection efficiency with the small plasmid (~ 90%) and the large one (~ 80%) into HEK 293T cells, even better than its backbone. We propose that the presence of metal-coordinated His ligand, redox-responsive S–S bonds, and the cationic polymer can synergistically provide robust DNA binding, efficient endosomal disruption, tolerance of serum protein adsorption, and low cytotoxicity. These new vectors could be promising for gene delivery and may be therapeutically relevant.

AB - Despite significant advancements in gene delivery and CRISPR technology, several challenges remain. Chief among these are overcoming serum inhibition and achieving high transfection efficiency with minimal cytotoxicity. To address these issues, there is a need for novel vectors that exhibit lower toxicity, maintain stability in serum-rich environments, and effectively deliver plasmids of various sizes across diverse cell types. In this study, to convert common polyethylenimine (PEI1.8k) into high-performance DNA delivery vectors, an innovative multifunctional vector was constructed based on histidine linked to PEI1.8k by redox-responsive disulfide bonds. Apart from highly efficient transfection of both small and large plasmids into HEK 293T (Human Embryonic Kidney 293T cells) with negligible cytotoxicity, PEI1.8k-S-S-His showed great transfection potential even at low plasmid doses (0.5 µg), as well as at serum concentrations ranging from 5 to 30% into HEK 293T cells, and achieved excellent plasmid transfection into NIH/3T3 (Mouse Embryonic Fibroblast cells), and MCF7 (Human Breast Cancer cells). Additionally, several metals were tested (Co, Cu, Cd, Ni, Zn, and Mn) to promote the plasmid packaging functionality and improve transfection efficiency. We observed that, in comparison to PEI1.8k-S-S-His, the manganese-functionalized nanocarrier (PEI1.8k-S-S-His-Mn) could transfect a large plasmid with equal efficiency (~ 30%) into MSCs (Mesenchymal Stem Cells). Interestingly, PEI1.8k-S-S-His-Mn showed higher transfection efficiency with the small plasmid (~ 90%) and the large one (~ 80%) into HEK 293T cells, even better than its backbone. We propose that the presence of metal-coordinated His ligand, redox-responsive S–S bonds, and the cationic polymer can synergistically provide robust DNA binding, efficient endosomal disruption, tolerance of serum protein adsorption, and low cytotoxicity. These new vectors could be promising for gene delivery and may be therapeutically relevant.

KW - Efficient plasmid delivery

KW - High serum tolerance

KW - Histidine-modified polymer

KW - Metal-coordinated histidine polymer

KW - Redox-responsive disulfide linker

UR - https://www.scopus.com/pages/publications/85217193632

U2 - 10.1007/s12033-024-01360-x

DO - 10.1007/s12033-024-01360-x

M3 - Article

C2 - 39806116

AN - SCOPUS:85217193632

SN - 1073-6085

VL - 68

SP - 170

EP - 186

JO - Molecular Biotechnology

JF - Molecular Biotechnology

IS - 1

ER -

Metal-Coordinated Histidine-Functionalized Redox-Responsive Polyethyleneimine as a Smart Gene Delivery Vector

Abstract

UN SDGs

Keywords

ASJC Scopus subject areas

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