Abstract

Mucus, a viscoelastic gel composed of dense mucin glycoprotein networks, acts as a major barrier to therapeutic delivery across all epithelial surfaces by trapping nanoparticles (NPs) and preventing access to the underlying cells. To address this, we developed mucus-evading yet cell-sticky (MECS) NPs with tunable surface charge using Flash NanoPrecipitation. These 100-nanometer-diameter MECS NPs incorporate a small amount (5 wt %) of polycationic dimethylaminoethyl methacrylate (PDMAEMA) into a dense, neutral poly(ethylene glycol) (PEG) corona, which enables mucus penetration while also driving epithelial cell adhesion. In vitro cell culture and physiologically relevant gut-on-a-chip organoids demonstrate MECS NPs penetrate mucus as effectively as purely PEGylated control NPs, while exhibiting a 45-fold increase in binding to epithelial cells. This dual functionality represents a generalizable strategy for overcoming the long-standing trade-off between mucodiffusion and cellular uptake in mucosal drug delivery.