Engineered microparticle morphology for enhanced intestinal retention in oral drug delivery

Microparticle-based drug delivery systems have gained widespread recognition for their ability to enable sustained drug release. However, their utility in oral administration has been constrained by suboptimal gastrointestinal retention. This study systematically evaluated how engineered microparticle morphology and surface topography influence intestinal adhesion dynamics and drug release profiles. Through controlled modulation of surface roughness and particle geometry, we demonstrated that non-spherical architectures, particularly waterdrop-like microparticles (WDMPs), exhibited superior mucoadhesive properties, achieving 1.25-fold prolonged gastrointestinal retention time while maintaining optimal drug release kinetics (71.2% cumulative release over 10 h). In a murine inflammatory bowel disease (IBD) model, dexamethasone (DXM)-loaded WDMPs outperformed conventional free drug administration, manifesting in significantly improved therapeutic outcomes: 1.16-fold enhanced weight recovery, 1.27-fold greater colon length preservation, and superior histopathological scores. Notably, WDMPs also boosted oral bioavailability of micronutrients by 1.2-to-1.6-fold, highlighting its dual applicability for both pharmaceutical and nutraceutical delivery. These comprehensive findings positioned WDMPs as a transformative oral delivery platform that addresses longstanding challenges in gastrointestinal drug absorption, offering substantial potential for clinical translation. STATEMENT OF SIGNIFICANCE: This study demonstrates the potential of engineered microparticle morphology to address key challenges in oral drug delivery. By investigating the effects of particle morphology and surface topography on intestinal retention and drug release, we show that non-spherical, rough microparticles exhibit enhanced mucoadhesion and sustained drug release. Waterdrop-like Microparticles (WDMPs) provide a significant improvement in gastrointestinal retention and drug release kinetics. WDMPs also outperform free dexamethasone in a murine model of inflammatory bowel disease. Additionally, WDMPs enhance oral bioavailability for micronutrients, offering dual-purpose potential for pharmaceutical and nutraceutical applications. These findings highlight the critical role of microparticle morphology in optimizing drug delivery efficiency and underscore the versatility of WDMPs as a customizable platform for controlled release therapies.