BiomaterialsJul 9, 2026

Targeted delivery of optimized mRNA nanoparticles to lymph nodes for COVID-19 vaccination

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Jul 10, 2026

Abstract

The peptide-nanocomplex demonstrated stable particle formation under 200 nm and retained mRNA expression for up to 7 days in vivo.

Lipid nanoparticles (LNPs) often accumulate in the liver and show transient protein expression, which can limit their effectiveness.
The developed peptide-nanocomplex is composed of three functional peptides, including an RNA-binding peptide, charge-modulating polyglutamic acid, and an APC-targeting cell-penetrating peptide with a new immune cell-binding motif.
The peptide-nanocomplex remained localized at the injection site and effectively drained to the lymph nodes, unlike LNPs.
Mice immunized with SARS-CoV-2 spike mRNA using the peptide-nanocomplex showed robust neutralizing antibody titers comparable to those from LNPs.
The peptide-nanocomplex induced significantly higher CD8+ T cell responses than LNPs.
No toxicity was observed in vivo after daily injections for two weeks at doses up to 200 times higher than safe levels.

Simplified

Messenger RNA (mRNA) vaccines require efficient delivery systems to reach antigen-presenting cells (APCs). Lipid nanoparticles (LNPs) are a standard delivery carrier. However, LNPs often accumulate in the liver and exhibit transient protein expression. These limitations can restrict their safety and immunogenic potential. Here, we developed a modular, peptide-based nanocomplex to overcome the current limitations. The system comprises three functional peptides: an RNA-binding peptide (RBP) for condensation, l-polyglutamic acid (PGA) for charge modulation, and an APC-targeting cell-penetrating peptide (A-CPP). This A-CPP features a newly discovered 7-mer immune cell-binding motif identified in this study. We optimized the physicochemical properties by systematically fine-tuning the ratios of these peptide modules. The optimized nanocomplex formed stable particles under 200 nm. Unlike LNPs, which showed significant liver accumulation, the peptide-nanocomplexes remained localized at the injection site and effectively drained to the lymph nodes. Furthermore, the peptide-nanocomplex retained mRNA expression for up to 7 days in vivo, whereas LNP-mediated expression diminished within 48 h. In mice immunized with SARS-CoV-2 spike mRNA, this prolonged antigen exposure elicited robust neutralizing antibody titers comparable to LNPs. Notably, the peptide-nanocomplex induced significantly higher CD8⁺ T cell responses than LNPs. Moreover, the peptide-nanocomplex demonstrated an excellent safety profile in vivo with no toxicity observed even after daily injections for two weeks at doses up to 200 times higher. This study establishes a data-driven fine-tuning strategy for peptide-based mRNA delivery. The resulting peptide-nanocomplex offers a safer, lymph node-targeted, and longer-lasting efficacy alternative to lipid-based carriers for next-generation vaccines.