Lipid Nanoparticle Surface Engineering with Heparosan Polysaccharides for Safe and Effective mRNA Delivery In Vitro and In Vivo

Lipid nanoparticles (LNPs) are clinically established carriers for nucleic acid therapeutics and mRNA-based vaccines. Current LNP formulations often use poly(ethylene glycol) (PEG)-based surface modifications to enhance pharmacokinetics, colloidal stability, and shelf life. However, PEG moieties can elicit anti-PEG immune responses, reactogenicity, and hypersensitivity reactions. Here, we investigated heparosan (HEP), a naturally occurring, biodegradable polysaccharide, for mRNA-LNP surface engineering and mRNA delivery in vitro and in vivo. We synthesized a library of HEP-coated LNPs and systematically characterized their physicochemical properties, including nanoparticle size, polydispersity, ζ potential, and mRNA encapsulation efficiency. We evaluated the delivery performance using two different mRNA payloads in both cultured cells and mouse models. Using HEP-engineered mRNA-LNPs, we demonstrate efficacy comparable to that of PEG-modified counterparts, with minimal tissue damage and negligible immune activation. In summary, our results highlight HEP as an immunologically silent, biocompatible coating agent that enables the formulation of colloidally stable LNPs for safe and effective mRNA delivery in vitro and in vivo, offering a potential path toward next-generation PEG-free nanomedicines.