The Interplay of Endosomal Escape and RNA Release from Polymeric Nanoparticles

Ribonucleic acid (RNA) nanocarriers, specifically lipid nanoparticles and polymeric nanoparticles, enable RNA transfection both in vitro and in vivo; however, only a small percentage of RNA endocytosed by a cell is delivered to the cytosolic machinery, minimizing its effect. RNA nanocarriers face two major obstacles after endocytosis: endosomal escape and RNA release. Overcoming both obstacles simultaneously is challenging because endosomal escape is usually achieved by using high positive charge to disrupt the endosomal membrane. However, this high positive charge typically also inhibits RNA release because anionic RNA is strongly bound to the nanocarrier by electrostatic interactions. Many nanocarriers address one over the other despite a growing body of evidence demonstrating that both are crucial for RNA transfection. In this review, we survey the various strategies that have been employed to accomplish both endosomal escape and RNA release with a focus on polymeric nanomaterials. We first consider the various requirements a nanocarrier must achieve for RNA delivery including protection from degradation, cellular internalization, endosomal escape, and RNA release. We then discuss current polymers used for RNA delivery and examine the strategies for achieving both endosomal escape and RNA release. Finally, we review various stimuli-responsive strategies for RNA release. While RNA release continues to be a challenge in achieving efficient RNA transfection, many new innovations in polymeric materials have elucidated promising strategies.