Hybrid lipid nanocapsules (hLNCs) represent a promising platform for mRNA delivery with the added benefit of ambient-temperature stabilization. Conventional hLNCs use polyethyleneimine (PEI) to facilitate mRNA binding, cellular uptake, and endosomal escape. However, PEI's high charge density is associated with cytotoxicity, nonspecific protein binding, and innate immune activation, features that may limit utility in chronic or repeat-dose applications. To overcome these limitations, we engineered the hLNC surface with either L-histidine (hLNC-Hist) or short-chain polyethylene glycol (hLNC-PEG) to improve biocompatibility. Both modifications reduced serum protein binding and enhanced cytocompatibility. hLNC-Hist preserved mRNA transfection in vitro and improved in vivo expression compared to unmodified hLNCs. In contrast, hLNC-PEG significantly reduced transfection efficiency. Notably, hLNC-Hist did not induce IgM or IgG responses and suppressed circulating pro-inflammatory cytokines following systemic administration - features that stand in contrast to the acute immune activation and anti-PEG antibody formation commonly observed with lipid nanoparticles (LNPs). Although hLNC-Hist did not achieve quite the peak transfection efficiency as LNPs in some models, hLNC-Hist did not exhibit the immunogenicity and reactogenicity that can limit repeated LNP dosing. hLNC-Hist offers a compelling alternative with an improved safety-efficacy profile for chronic mRNA delivery. Importantly, hLNC-Hist retained the ability to stabilize mRNA under ambient and elevated temperatures when embedded in sugar glass, enabling potential cold-chain-free deployment. These findings position hLNC-Hist as an immunologically silent, biocompatible, and thermally stable mRNA delivery vehicle. Its suitability for repeated administration makes it particularly attractive for emerging mRNA therapies requiring chronic dosing, including cancer immunotherapy, protein replacement, and autoimmune modulation.
