Optimizing Lipid Nanoparticles for Delivery in Primates

• Main Authors: Heyes, J. (Author), Lam, K. (Author), Leung, A. (Author), Lutwyche, P. (Author), Reid, S. (Author), Schreiner, P. (Author), Stainton, P. (Author), Yaworski, E. (Author)
• Format: Article
• Language: English
• Published: John Wiley and Sons Inc 2023
• Subjects: Controlled drug delivery; Human response; lipid nanoparticles; Lipid nanoparticles; Mammals; Messenger RNA; Nanoparticles; nanotechnology; Non-human primate; nucleic acid; particle size; Particle size; Particles sizes; PEG shielding; Polyethylene glycols; potency translation; Potency translation; Product design; RNA; RNA therapeutics; Small interfering RNA; Surface chemistry; Targeted drug delivery; Therapeutic; therapeutics
• Online Access: View Fulltext in Publisher

 Lipid nanoparticles (LNPs) are clinically proven to successfully deliver both small interfering RNA (siRNA) therapeutics and larger mRNA payloads for prophylactic vaccine applications. Non-human primates (NHPs) are generally considered to be the most predictive of human responses. However, for ethical and economic reasons, LNP compositions have historically been optimized in rodents. It has been difficult to translate LNP potency data from rodents to NHPs for intravenously (IV) administered products in particular. This presents a major challenge for preclinical drug development. An attempt to investigate LNP parameters, which have historically been optimized in rodents, is carried out, and seemingly innocuous changes are found to result in large potency differences between species. For example, the ideal particle size for NHPs (50–60 nm) is found to be smaller than for rodents (70–80 nm). Surface chemistry requirements are also different, with almost double the amount of poly(ethylene glycol) (PEG)-conjugated lipid needed for maximal potency in NHPs. By optimizing these two parameters, approximately eight-fold increase in protein expression from intravenously administered messenger RNA (mRNA)-LNP in NHP is gained. The optimized formulations are well tolerated when administered repeatedly with no loss of potency. This advancement enables the design of optimal LNP products for clinical development. © 2023 Genevant Sciences Corporation. Advanced Materials published by Wiley-VCH GmbH.