This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility: Researchers from the Yong Loo Lin School of Medicine, National University of Singapore (NUS Medicine), and Tianjin Medical University General Hospital have developed a bioinspired lipid nanoparticle (LNP) that can deliver gene-editing machinery to the liver and reduce low-density lipoprotein (LDL) cholesterol, commonly known as "bad" cholesterol. The nanoparticles reduced LDL and total cholesterol by more than 20% after two doses, while showing fewer signs of inflammation and toxicity than comparator formulations.
The findings were published in the Journal of Controlled Release. The research team designed the LNP using materials inspired by molecules naturally found in the body, with the aim of improving the safety of messenger RNA (mRNA) delivery. mRNA is a temporary set of genetic instructions that tells cells how to make a specific protein. Once the instructions have been used, the mRNA is naturally broken down by the body.
LNPs protect mRNA and transport it into cells, but some conventional formulations contain laboratory-made lipids that may trigger inflammation as they break down. To develop a potentially more biologically compatible carrier, the researchers combined naturally occurring polyamines with oleic acid, a fatty acid found in the body. The strongest-performing candidate, agmatine-oleic acid, or Agm-oa, carried and protected about 98% of its mRNA payload and delivered it effectively to cultured liver cells and laboratory models.
Following administration, the nanoparticles accumulated mainly in the liver. "Many studies focus primarily on the therapeutic cargo, but how that cargo is delivered is equally important," said Assistant Professor Jiong-Wei Wang, Department of Surgery and Department of Physiology, and the Cardiovascular-Metabolic Disease Translational Research Programme at NUS Medicine, who led the research. "Our aim was to develop a delivery platform using building blocks inspired by endogenous metabolites, which are molecules our bodies naturally produce or use.
By considering what happens to the nanoparticle after it has delivered its payload, we hope to create RNA delivery systems that are not only effective, but also more biologically compatible." The team used the nanoparticles to deliver an adenine base editor targeting PCSK9, a gene that regulates LDL cholesterol. Reducing PCSK9 activity allows more LDL receptors to remain on liver cells, helping the liver remove cholesterol from the bloodstream. In cultured cells, the nanoparticles edited about 68% of the intended PCSK9 target.
No unintended changes were detected at the six most likely off-target sites examined, although broader genome-wide testing is still required. In laboratory models fed a high-fat diet, two intravenous doses given one week apart reduced LDL and total cholesterol by more than 20% compared with untreated models and those given RNA without the nanoparticle carrier. "PCSK9 is a well-established target for lowering LDL cholesterol, but effective gene editing depends on delivering the editor safely and efficiently to the liver," said Professor Xin Zhou, a senior cardiologist in the Department of Cardiology, Tianjin Medical University General Hospital.
Extract — continue reading at the source.
