This review discusses the challenges and recent advancements in delivering drugs and genes to mucosal tissues using mucus-penetrating nanoparticles (MPPs). Mucus, a viscoelastic and adhesive gel, effectively traps foreign particles due to steric obstruction and adhesion, limiting the duration of sustained drug delivery. The review highlights the properties of mucus that hinder particle penetration, such as its high viscosity and the formation of polyvalent adhesive interactions with mucin fibers. It also reviews the design and development of MPPs that can avoid rapid mucus clearance mechanisms, including the use of muco-inert polymers like polyethylene glycol (PEG) to reduce particle adhesion. The study demonstrates that MPPs can rapidly traverse physiological human mucus, offering hope for improved efficacy and reduced side effects in various therapeutic applications. The review further explores the implications of particle size on mucosal transport and the potential for large PEGylated nanoparticles to efficiently deliver therapeutics to mucosal surfaces.This review discusses the challenges and recent advancements in delivering drugs and genes to mucosal tissues using mucus-penetrating nanoparticles (MPPs). Mucus, a viscoelastic and adhesive gel, effectively traps foreign particles due to steric obstruction and adhesion, limiting the duration of sustained drug delivery. The review highlights the properties of mucus that hinder particle penetration, such as its high viscosity and the formation of polyvalent adhesive interactions with mucin fibers. It also reviews the design and development of MPPs that can avoid rapid mucus clearance mechanisms, including the use of muco-inert polymers like polyethylene glycol (PEG) to reduce particle adhesion. The study demonstrates that MPPs can rapidly traverse physiological human mucus, offering hope for improved efficacy and reduced side effects in various therapeutic applications. The review further explores the implications of particle size on mucosal transport and the potential for large PEGylated nanoparticles to efficiently deliver therapeutics to mucosal surfaces.