Lipid nanoparticles (LNPs) with reversibly attached branched lipid tails for the delivery of mRNA for gene therapy. Problem: Delivery of mRNA to target cells enables the expression of engineered proteins but mRNA is unstable and negatively charged, necessitating a delivery vehicle to ensure its entry into cells. LNPs can ferry mRNA across the cell membrane, but their key component - lipidoid - can be difficult to synthesize, and their efficacy in delivering mRNA is variable. LNPs with degradable alkyl branched tails have been found to improve cell penetration, but these lipids are difficult to synthesize due to a lack of commercially available branched building blocks. Solution: A combinatorial method for one-pot, high-throughput, and cost-effective production of a wide variety of lipidoids with variable headgroups, body tails, and branch tails. Using this method, they create a lipidoid with “space-shuttle resembling” branched alkyl tails with degradable linkers. These tails dramatically improve mRNA delivery by enhancing endosomal escape, increasing the mRNA delivered to the cell's translation machinery. The addition of these tails to inefficacious lipidoids can increase mRNA delivery by up to three orders of magnitude. This greatly improves therapeutic protein expression. Nanoparticles created with these lipidoids would, therefore, improve outcomes for several gene therapy applications, including vaccines and cancer therapeutics. Technology: This method can be used to rapidly synthesize branched lipidoids for the construction of LNPs. LNPs sequester negatively charged mRNA and facilitate entry into the cell via their neutral charge and hydrophobic alkyl tails. The escape of the LNPs from the cell to deliver mRNA to translation machinery is facilitated by branched tails that can then detach to promote mRNA delivery, like booster rockets detaching from a space shuttle. Using a one-pot, two-step, three-component reaction, the inventors synthesized a library of lipidoids with branched tails connected via a degradable linker. This synthetic strategy is highly efficient, producing over 80% yield, with easily removable dichloromethane or triethylamine solvents, and with byproducts easily quenched with ethanol. Advantages:
Stage of Development:
(A) Depiction of space shuttle-inspired strategy to enhance lipid nanoparticle mRNA delivery via the addition of branched tails with degradable linkers. Degradation of these linkers and detachment of the branched tails facilitates mRNA delivery, increasing translation efficiency and therapeutic protein expression. Intellectual Property: Intellectual Property:
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Docket #23-10491