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 - 2025
Y1 - 2025
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 - http://www.scopus.com/inward/record.url?scp=85217193632&partnerID=8YFLogxK
U2 - 10.1007/s12033-024-01360-x
DO - 10.1007/s12033-024-01360-x
M3 - Article
C2 - 39806116
AN - SCOPUS:85217193632
SN - 1073-6085
JO - Molecular Biotechnology
JF - Molecular Biotechnology
M1 - 445101
ER -