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- Conflict of Interest
- In relation to this article, we declare that there is no conflict of interest.
- Publication history
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Received January 8, 2026
Accepted May 29, 2026
Available online October 25, 2026
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This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/bync/3.0) which permits
unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Development of a Polyethylenimine-based Multimeric Polymer for Efficient mRNA Delivery
https://doi.org/10.1007/s11814-026-00765-5
Abstract
Messenger RNA (mRNA) has emerged as a versatile therapeutic platform due to its capacity for rapid and transient protein
expression without the risk of genomic integration. Nonetheless, its clinical application remains limited by poor stability,
large molecular size, and inefficient cellular uptake, underscoring the need for safe and effective non-viral carriers. In
this study, we developed and characterized a series of PEI-graft-PEI (0.8 kDa and 2 kDa) polymers (PgP) engineered to
provide an optimal balance between mRNA condensation efficiency, intracellular trafficking, and biocompatibility. PgP
0.8 kDa and PgP 2 kDa were synthesized via controlled Michael addition and amidation reactions, and their structures
were confirmed using 1
H nuclear magnetic resonance and Fourier transform infrared spectroscopy. The polymer exhibited
a broad buffering capacity comparable to that of its higher-molecular-weight analog (polyethylenimine 25 kDa), efficiently
condensed mRNA into stable, positively charged nanostructures, and demonstrated high encapsulation efficiency. Confocal
microscopy revealed strong cellular internalization and cytosolic accumulation of PgP/mRNA polyplexes in NIH3T3 cells.
Transfection studies showed that PgP achieved luciferase expression levels approaching those of polyethylenimine 25 kDa
while maintaining markedly improved cytocompatibility (>90% viability). Although PgP 2 kDa exhibited stronger mRNA
condensation and higher transfection efficiency, PgP 0.8 kDa demonstrated exceptional biocompatibility and adequate
delivery performance. This superior safety profile makes PgP 0.8 kDa a promising next-generation nonviral mRNA carrier
for therapeutic applications that require minimal cytotoxicity and high tolerability
