Tannic Acid Lipid Nanoparticles can Deliver Messenger RNA Payloads and Improve their Endosomal Escape

Abstract Even though lipid nanoparticles (LNPs) can deliver messenger RNA (mRNA) payloads into cells, their efficiency is often limited by endosomal trapping which prevents RNA payloads from acting therapeutically. Improving the percentage of RNA LNPs that can escape from endosomes and enter the cytoplasm is therefore an area of active research interest that could lead to improved safety profiles and reduced manufacturing costs of mRNA drugs. Here, tannic acid mRNA LNPs [TA(+) mRNA LNPs] are reported as an effective delivery platform for the delivery of mRNA payloads. The formulation, characterization, and stability of TA(+) mRNA LNPs are described; two different approaches via confocal microscopy are then utilized to quantify the endosomal escape of the TA(+) mRNA LNPs; and lastly, the biodistribution and tolerability of the TA(+) mRNA LNPs are evaluated in mice following intravenous and intramuscular dosing regimens. To isolate the effect that TA imparts on each of these properties, mRNA LNPs that do not contain TA [TA(−) mRNA LNPs] are evaluated side‐by‐side in each of these studies. A collective analysis of these results suggests that TA(+) mRNA LNPs are effective carriers for mRNA payloads and that the incorporation of TA within each formulation improves the endosomal escape of mRNA LNPs.