Design Principles of Oral Nanomedicines to Overcome the Delivery Barriers

Oral nanomedicines provide a promising, noninvasive drug delivery platform, offering advantages in patient compliance and ease of administration. However, their clinical translation for both gastrointestinal (GI) and extra-GI diseases is hampered by multiple physiological and pharmacokinetic barriers, including the harsh GI environment, poor translocation across the mucus and epithelial layers, rapid hepatic and renal clearance, limited tissue accumulation, inefficient cellular uptake, insufficient lysosome escape, and suboptimal intracellular drug release. These challenges collectively result in low oral bioavailability and limited therapeutic outcomes. This review provides a comprehensive overview of recent advances in oral nanomedicines, delineating six key attributes for effective GI-targeted drug delivery and eight design principles for systemic applications. We also discuss the translational bottlenecks and highlight the emerging strategies to overcome these barriers, offering insights into the integration of oral nanotherapeutics into precision medicine.