Mucus is a viscoelastic and adhesive gel that protects mucosal surfaces such as the lungs, gastrointestinal tract, and eyes. Conventional drug delivery systems are often trapped by mucus due to steric obstruction or adhesion, limiting their effectiveness. This review discusses the challenges of delivering drugs and genes to mucosal tissues and the development of mucus-penetrating nanoparticles (MPPs) that can bypass these barriers. MPPs are designed to avoid adhesion to mucin fibers and are small enough to navigate mucus layers efficiently. Recent studies show that nanoparticles coated with muco-inert polymers can rapidly traverse mucus, with diffusion rates comparable to those in water. This suggests that MPPs can enable sustained drug delivery at mucosal surfaces. The review also highlights the importance of understanding mucus composition, thickness, and clearance times to design effective delivery systems. Mucus is composed of mucin fibers, proteoglycans, and other components, creating a complex environment that hinders particle transport. The development of MPPs is crucial for improving drug delivery to mucosal tissues, as conventional nanoparticles are often trapped by mucus. The review discusses the mechanisms of particle transport in mucus, including the role of hydrophobic interactions and the importance of surface chemistry in enabling mucus penetration. The use of polyethylene glycol (PEG) coatings has shown promise in reducing particle-mucus interactions and enhancing transport. The findings suggest that MPPs can significantly improve the efficacy of drug and gene delivery to mucosal tissues.Mucus is a viscoelastic and adhesive gel that protects mucosal surfaces such as the lungs, gastrointestinal tract, and eyes. Conventional drug delivery systems are often trapped by mucus due to steric obstruction or adhesion, limiting their effectiveness. This review discusses the challenges of delivering drugs and genes to mucosal tissues and the development of mucus-penetrating nanoparticles (MPPs) that can bypass these barriers. MPPs are designed to avoid adhesion to mucin fibers and are small enough to navigate mucus layers efficiently. Recent studies show that nanoparticles coated with muco-inert polymers can rapidly traverse mucus, with diffusion rates comparable to those in water. This suggests that MPPs can enable sustained drug delivery at mucosal surfaces. The review also highlights the importance of understanding mucus composition, thickness, and clearance times to design effective delivery systems. Mucus is composed of mucin fibers, proteoglycans, and other components, creating a complex environment that hinders particle transport. The development of MPPs is crucial for improving drug delivery to mucosal tissues, as conventional nanoparticles are often trapped by mucus. The review discusses the mechanisms of particle transport in mucus, including the role of hydrophobic interactions and the importance of surface chemistry in enabling mucus penetration. The use of polyethylene glycol (PEG) coatings has shown promise in reducing particle-mucus interactions and enhancing transport. The findings suggest that MPPs can significantly improve the efficacy of drug and gene delivery to mucosal tissues.