Emerging nanotechnology-enabled siRNA oral delivery platforms

Utilization of endogenous RNA interference (RNAi) mechanisms via delivery of exogeneous small interfering RNA (siRNA) molecules offers a transformative approach to treatment of disease by enabling sequence specific silencing of mutated gene expression. Nanotechnology-based platforms have enabled delivery of siRNA and have already been clinically validated for intravenous (IV) infusion administration (e.g patisiran). Oral administration of siRNA remains an unmet challenge due to formidable biological barriers in the gastrointestinal (GI) tract. Nanotechnology-enabled strategies for oral siRNA delivery have emerged as a powerful solution to overcoming these biological barriers for effective gene silencing. This review provides a comprehensive overview of GI barriers for siRNA delivery as well as highlights recent advances in nanoparticle platforms for oral siRNA delivery. In addition, this review explores translational considerations and highlights the potential of oral siRNA nanomedicines to reduce dependence on invasive parenteral delivery and costly monoclonal antibody therapies. Together, these advances outline a promising path toward clinically viable, patient-friendly siRNA therapeutics delivered orally. Literature for this review was identified through database searches [University of New Mexico University Libraries, Web of Science, Google Scholar, and PubMed databases April 2025-November 2025] as it related to the oral delivery of nanoparticles, siRNA-loaded nanoparticles, gene therapy, and related nanomedicine delivery strategies.