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<p>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&#xa0;kDa and 2&#xa0;kDa) polymers (PgP) engineered to provide an optimal balance between mRNA condensation efficiency, intracellular trafficking, and biocompatibility. PgP 0.8&#xa0;kDa and PgP 2&#xa0;kDa were synthesized via controlled Michael addition and amidation reactions, and their structures were confirmed using <sup>1</sup>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&#xa0;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&#xa0;kDa while maintaining markedly improved cytocompatibility (&gt; 90% viability). Although PgP 2&#xa0;kDa exhibited stronger mRNA condensation and higher transfection efficiency, PgP 0.8&#xa0;kDa demonstrated exceptional biocompatibility and adequate delivery performance. This superior safety profile makes PgP 0.8&#xa0;kDa a promising next-generation nonviral mRNA carrier for therapeutic applications that require minimal cytotoxicity and high tolerability.</p> Graphical Abstract <p></p>

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Development of a Polyethylenimine-based Multimeric Polymer for Efficient mRNA Delivery

  • 期刊论文

  • 发表日期：

    2026年6月16日

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  • Seongyeon Kim,
  • Onesun Jung,
  • Viet Dongquoc,
  • Minyoung Choi,
  • Sangik Hwang,
  • Ji Heon Noh,
  • Le Thi Thuy,
  • Joon Sig Choi

摘要

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 1H 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.

Graphical Abstract