Modular Peptide Coatings Regulate the Multistep Biological Performance of Lipid Nanoparticles for Enhanced mRNA Delivery

Abstract Lipid nanoparticles (LNPs) are a leading platform for mRNA delivery, yet improving their performance often requires complex chemical modification or reformulation of core components. Here, we report a modular peptide-coating strategy for post-formulation engineering of LNP interfaces through physical assembly. A modular multifunctional peptide (MFP) library was developed to systematically investigate how peptide composition, secondary structure, chirality, and concentration regulate coating assembly and delivery performance. In vitro, MFP coatings enhanced cellular uptake, endosomal escape, and mRNA translation. In vivo, optimized coatings improved mRNA delivery across multiple LNP formulations and promoted receptor-mediated tumor-specific accumulation and expression. In an IL-12 mRNA immunotherapy model, MFP-coated LNPs elicited potent antitumor immune responses and inhibited tumor growth without observable systemic toxicity. This work establishes a modular peptide surface engineering strategy for regulating LNP biological performance and provides an expandable framework for developing a tissue- and disease-specific nanomedicine platform through the tailoring of peptide functional modules.