Hybrid lipid-nanogels: nanolipogels for mRNA delivery.

Nanoscale drug-delivery systems are central to translating mRNA and other biologic medicines into affordable, scalable products. Existing lipid- and polymer-based carriers are often constrained by costly multi-step syntheses, batch variability and acute immune responses driven by ionisable lipids. Here, we report nanolipogels (NLGs), a hybrid phospholipid-polymer carrier built around a synthetic phospholipid, phosphatidylbutenol, synthesised in a single enzyme-catalysed transphosphatidylation step from 1,2-dioleoyl-sn-glycero-3-phosphocholine. The reactive vinyl-terminated headgroup permits aqueous, one-pot free-radical co-polymerisation with either the permanently charged cationic comonomer 2-(acryloyloxy)ethyl trimethylammonium chloride (AETC) or the pH-responsive comonomer 2-(dimethylamino)ethyl methacrylate (DMAEMA), facilitating the electrostatic loading of mRNA. The resulting NLGs are sub-200 nm in size, encapsulate green fluorescent protein (GFP) mRNA with efficiencies above 75%, and exhibit sustained mRNA release over seven days in the presence of 10 mM glutathione. In HeLa and brain endothelial bEnd.3 cells, NLGs showed cell viability comparable to optimised liposomal controls and substantially higher than that observed with Lipofectamine 2000, while DMAEMA-NLGs produced a ∼10.9-fold increase in GFP fluorescence over Lipofectamine 2000. The combination of benign, scalable chemistry with efficient mRNA delivery positions NLGs as a promising platform for accessible nanomedicine.