Peptide-nanocomplex delivers SARS-CoV-2 mRNA to lymph nodes, boosting CD8+ T cells and safety over LNPs.

Messenger RNA (mRNA) vaccines offer a powerful platform for immunization, but their efficacy hinges on efficient delivery to antigen-presenting cells (APCs). Current standard-of-care lipid nanoparticles (LNPs), while effective, face limitations including significant accumulation in the liver and transient protein expression, which can compromise both safety and long-term immunogenic potential. Addressing these challenges, researchers are exploring alternative delivery systems that can offer improved biodistribution and sustained antigen presentation, aiming for enhanced immune responses and a safer profile.

Researchers developed a modular peptide-based nanocomplex designed for efficient mRNA delivery. This system comprises three key functional peptides: an RNA-binding peptide (RBP) for mRNA condensation, l-polyglutamic acid (PGA) for charge modulation, and an APC-targeting cell-penetrating peptide (A-CPP) featuring a newly identified 7-mer immune cell-binding motif. They systematically fine-tuned the ratios of these peptide modules to optimize physicochemical properties. The optimized nanocomplexes were then tested in mice immunized with SARS-CoV-2 spike mRNA, comparing their performance against traditional LNP carriers across various parameters including particle stability, biodistribution, mRNA expression duration, neutralizing antibody titers, CD8+ T cell responses, and in vivo toxicity.

The optimized peptide-nanocomplexes formed stable particles under 200 nm. Crucially, unlike LNPs which showed significant liver accumulation, the peptide-nanocomplexes remained localized at the injection site and effectively drained to the lymph nodes. This improved biodistribution correlated with prolonged antigen expression; 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, but notably induced significantly higher CD8+ T cell responses. Furthermore, 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 than typical.