The study investigates the transport of large polymeric nanoparticles in fresh, undiluted human mucus, specifically cervicovaginal (CV) mucus. Despite the common belief that nanoparticles larger than 10-200 nm cannot diffuse through mucus barriers, the researchers found that large nanoparticles (500 and 200 nm in diameter) coated with polyethylene glycol (PEG) diffused through mucus with an effective diffusion coefficient only 4- and 6-fold lower than in water. In contrast, smaller uncoated nanoparticles (100 nm) had a diffusion coefficient 2,400- to 40,000-fold lower in mucus than in water. The results suggest that large nanoparticles, if properly coated, can rapidly penetrate physiological human mucus, offering potential for mucosal drug delivery. The study also highlights the importance of particle concentration and surface chemistry in mucus transport, and provides insights into the structure and properties of CV mucus.The study investigates the transport of large polymeric nanoparticles in fresh, undiluted human mucus, specifically cervicovaginal (CV) mucus. Despite the common belief that nanoparticles larger than 10-200 nm cannot diffuse through mucus barriers, the researchers found that large nanoparticles (500 and 200 nm in diameter) coated with polyethylene glycol (PEG) diffused through mucus with an effective diffusion coefficient only 4- and 6-fold lower than in water. In contrast, smaller uncoated nanoparticles (100 nm) had a diffusion coefficient 2,400- to 40,000-fold lower in mucus than in water. The results suggest that large nanoparticles, if properly coated, can rapidly penetrate physiological human mucus, offering potential for mucosal drug delivery. The study also highlights the importance of particle concentration and surface chemistry in mucus transport, and provides insights into the structure and properties of CV mucus.