Lipid nanoparticles (LNPs) have become the most widely used non-viral delivery system for mRNA therapeutics, with successful clinical applications in vaccines and gene editing. However, a major hurdle remains: conventional LNPs tend to accumulate in the liver, even after local administration. This liver bias limits their effectiveness for treatments that need to act locally, such as in muscle, brain, or eye, and raises concerns about off-target effects.
Changing the lipid recipe
To solve this problem, the researchers used a statistical method called design of experiments to work out which ingredients and proportions shaped delivery. This approach helped them examine combinations of changes and progressively refine the formulation. They retained SM102, the main delivery lipid, replaced cholesterol with the plant sterol beta-sitosterol, and adjusted the amounts of a helper phospholipid and a polyethylene glycol (PEG) lipid. In mice, SM102M reduced liver signal by about 80 times after intramuscular injection and about 72 times after intravenous injection, while keeping strong local expression.
Why does the new formulation reduce liver accumulation?
Further experiments provided clues to how SM102M alters delivery. Its nanoparticles differ in shape, escape intracellular compartments in liver cells less efficiently, remain in the body for less time, and bind less strongly to ApoE, a protein that promotes liver targeting. Despite reduced liver targeting, SM102M delivers mRNA more efficiently into cultured cells.
Maintaining delivery over repeated doses
Because mRNA provides temporary instructions, many potential treatments may require repeated administration. When given multiple times, SM102M maintained strong local expression and low liver signal. The original SM102 lost much of its local effect. SM102M also triggered less anti-PEG IgG, which may reduce immune reactions after repeated use.
Local delivery beyond muscle
Experiments in the brain and eye showed similar benefits. Following injection into a brain ventricle or the vitreous cavity of the eye, SM102M produced expression concentrated in the intended region, with less unwanted liver expression than the reference formulation.
These findings show how adjusting the lipid recipe can improve the precision of local mRNA delivery. Further studies using therapeutic mRNA and disease models will be needed to establish treatment benefits and longer-term safety before human use.
Science China Life Sciences
Experimental study