Oral Delivery of siRNA Using Fluorinated, Small-Sized Nanocapsules Toward Anti-Inflammation Treatment.

Oral delivery of siRNA provides a promising paradigm for treating diseases that require regular injections. However, the multiple gastrointestinal and systemic barriers often lead to inefficient oral absorption and low bioavailability of siRNA. Technologies that can overcome these barriers are still lacking, which hurdles the clinical potential of orally delivered siRNA. Herein, small-sized, fluorinated nanocapsules (F-NCs) were developed to mediate efficient oral delivery of TNF-α siRNA for anti-inflammation treatment. The NCs possessed a disulfide-cross-linked shell structure, thus featuring robust stability in the gastrointestinal tract. Because of their small size (∼30 nm) and fluorocarbon-assisted repelling of mucin adsorption, the best-performing F 3 -NCs showed excellent mucus penetration and intestinal transport capabilities without impairing the intestinal tight junction, conferring the oral bioavailability of 20.4% in relative to i.v. injection. The disulfide cross-linker could be cleaved inside target cells, causing NCs dissociation and siRNA release to potentiate the TNF-α silencing efficiency. In murine models of acute and chronic inflammation, orally delivered F 3 -NCs provoked efficient TNF-α silencing and pronounced anti-inflammatory efficacies. This study therefore provides a transformative strategy for oral siRNA delivery, and would render promising utilities for anti-inflammation treatment. This article is protected by copyright. All rights reserved.