Salivary Enzyme-Responsive Switching Nanoparticles Overcoming Diffusion and Absorption Barriers for Transmucosal Delivery

Transmucosal drug delivery is an attractive noninvasive strategy, yet its efficiency is fundamentally limited by the trade-off between mucus penetration and mucoadhesion. Here, we present salivary enzyme-responsive penetration-to-adhesion switching nanoparticles (SEPAS NPs) designed to overcome this limitation in the context of buccal drug delivery. SEPAS NPs feature a dual-regime architecture consisting of an N -guanidinium chitosan oligosaccharide (G-COS) inner layer that provides mucoadhesion and a degradable starch-based outer layer that transiently shields cationic interactions with mucins during transport. Under mucus-mimicking conditions, SEPAS NPs exhibit minimal mucin binding during penetration, followed by enzyme-mediated degradation of the starch shell that exposes the underlying G-COS layer and enhances retention at a mucin-coated interface by approximately 6-fold. Furthermore, this switching design does not compromise drug release, maintaining diffusion-dominated sustained release of dexamethasone (DEX). In addition, SEPAS NPs demonstrate excellent cytocompatibility (>90% cell viability) and maintain the anti-inflammatory activity of released DEX. Collectively, this work presents an enzyme-responsive nanoparticle strategy that resolves the penetration–adhesion trade-off while maintaining favorable release kinetics and biocompatibility, providing a broadly adaptable platform for transmucosal drug delivery across diverse mucus environments.