Surface Chemistry-Driven Permeation of Nanoparticles Produced by Flash Nanoprecipitation through Mucus Barriers

Mucosal barriers protect epithelial tissues but limit the diffusion of therapeutic nanoparticles, posing a major challenge for transmucosal drug delivery. Surface chemistry plays a key role in navigating this barrier, where both mucoadhesive and mucopenetrating strategies have shown value. In this study, we demonstrate how combining zwitterionic and boronic acid functionalities enables the rational design of nanoparticles with tunable interactions toward mucus. Block copolymers of poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) and poly(carboxybetaine) (PMCB), with or without a terminal aminophenylboronic acid (APBA), were synthesized and used as nanoparticle stabilizers via flash nanoprecipitation using a multi-inlet vortex mixer. Nanoparticle permeation was examined in purified sheep small intestine mucus. PMPC-based nanoparticles exhibited superior transport compared to PMCB- and PEG-containing analogs. Increasing APBA density led to reduced permeation due to specific interactions with mucin-associated sialic acids; this effect was reversed upon preincubation with free sialic acid. Zeta potential analysis before and after mucus exposure confirmed preserved surface integrity regardless of APBA density. These findings highlight the ability to balance mucoadhesive and mucopenetrating properties via surface chemistry, offering a flexible platform for engineering nanoparticles optimized for mucus barrier traversal and downstream targeting in transmucosal drug delivery.