Development of an Inhalable DNA Tetrahedron MicroRNA Sponge

Abstract In designing aerosolized drugs, the challenge lies in achieving optimal penetration and retention. Existing delivery systems prioritize larger particles for prolonged intrapulmonary retention, compromising penetration speed. Conversely, smaller nanoparticles face rapid clearance and limited retention. RNA sponges featuring multiple microRNA binding sites exhibit promising potential for gene expression regulation. However, the complex structure of the frequently utilized cyclic RNA sponge impedes rapid penetration and cellular uptake, restricting its application. This study proposes an innovative approach using a compact tetrahedral framework of nucleic acid to construct an inhalable microRNA sponge. Distinguished by its simplified structure, this microRNA sponge ensures effective microRNA inhibition, rapid tissue penetration, and prolonged residency through prompt endocytosis. Validated in acute lung inflammation models, the approach demonstrates swift restoration of local immune homeostasis. This design addresses the critical need for aerosol vehicles that balance efficient penetration and sustained retention, offering a promising solution for effective gene expression regulation.