Oral delivery of nucleic acid therapeutics: Challenges, strategies, and opportunities

•Oral nucleic acid therapeutics have an edge in gastrointestinal disease treatment.•Inherent physicochemical properties of nucleic acids and multiple gastrointestinal barriers hinder oral nucleic acid delivery.•Nanoparticle-based strategies allowed enhanced delivery efficacy and improved therapeutic outcomes.•Extensive studies on exploring the mechanism of orally delivered nucleic acids is in urgent need for future development. In recent decades, advances in chemical synthesis and delivery systems have accelerated the development of therapeutic nucleic acids, several of which have been approved by the Us Food and Drug Administration (FDA). Oral nucleic acid delivery is preferred because of its simplicity and patient compliance, but it still presents distinct challenges. The negative charge, hydrophilicity, and large molecular weight of nucleic acids combined with in vivo gastrointestinal (GI) barriers (e.g., acidic pH, enzymes, mucus, and intestinal epithelial cells) severely hinder their delivery efficacy. Recently, various nanoparticles (NPs), ranging from polymeric to lipid-based (L)NPs and extracellular vesicles (EVs), have been extensively explored to address these obstacles. In this review, we describe the physiological barriers in the GI tract and summarize recent advances in NP-based oral nucleic acid therapeutics.