The Effect of Size and Shape of RNA Nanoparticles on Biodistribution.

Drugs with ideal pharmacokinetic profile require long half-life but little organ accumulation. Generally, PK and organ accumulation are contradictory factors: smaller size leads to faster excretion and shorter half-lives and thus a lower tendency to reach targets; larger size leads to longer circulation but stronger organ accumulation that leads to toxicity. Organ accumulation has been reported to be size dependent due in large part to engulfing by macrophages. However, publications on the size effect are inconsistent because of complication by the effect of shape that varies from nanoparticle to nanoparticle. Unique to RNA nanotechnology, size could be tuned without a change in shape, resulting in a true size comparison. Here we investigated size effects using RNA squares of identical shape but varying size and shape effects using RNA triangles, squares, and pentagons of identical size but varying shape. We found that circulation time increased with increasing RNA nanoparticle size from 5-25 nm, which is the common size range of therapeutic RNA nanoparticles. Most particles were cleared from the body within 2 hr after systemic injection. Undetectable organ accumulation was found at any time for 5 nm particles. For 20 nm particles, weak signal was found after 24 hr, while accumulation in tumor was strongest during the entire study.