ArticlebioRxiv : the preprint server for biology2026
Peptide additives reprogram the lipid nanoparticle corona and enhance gene delivery in a serum-free environment for lung epithelium.
Article in bioRxiv : the preprint server for biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Lipid nanoparticles (LNPs) have become a clinical standard for systemically-administered nucleic acid drugs and vaccines, but the LNP pipeline for locally-delivered LNP therapies remains much less mature. Local delivery in lung represents a particularly compelling application space for DNA-LNP therapeutics, as local gene therapies could support sustained epithelial recovery and functional restoration in various lung diseases. However, locally-delivered DNA-LNPs face multiple barriers, including the limited availability of serum components that often support conventional LNP activity, and the additional delivery barriers posed by the nucleus. We generated hybrid peptide-lipid nanoparticles (hpLNPs) for pulmonary DNA delivery by using a core-shell assembly strategy to incorporate short histone-derived peptides, selected for their DNA-transport capacity, into a clinically inspired LNP formulation. In parallel, we evaluated serum pre-coating of LNPs as a strategy to boost hpLNP activity in the serum-poor airway environment. A peptide:DNA amine/phosphate (N/P) ratio of 0.9 was identified as the highest feasible ratio to permit peptide incorporation into hpLNPs while preserving DNA encapsulation efficiency at >90%, retaining hpLNP colloidal stability, and preserving the overall pKa for LNPs. At N/P = 0.9, hpLNPs showed markedly enhanced DNA delivery in alveolar lung cells, achieving up to a 17‑fold increase in transgene expression compared to peptide‑free LNPs. Transgene expression levels varied depending on serum concentration, with expression peaking in the presence of 6% serum. Furthermore, serum pre-coating was necessary to enable
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