Mucus, a viscoelastic and adhesive gel, forms a significant barrier to the efficient delivery of therapeutic particles to mucosal surfaces. This barrier hinders the penetration of nanoparticles, leading to rapid clearance and reduced efficacy of treatments. To overcome this challenge, researchers have developed mucus-penetrating nanoparticles (MPPs) that can traverse the mucus layer efficiently. These particles are designed to avoid adhesion to mucin fibers and are small enough to navigate the dense fiber mesh. Recent studies have demonstrated that MPPs can rapidly traverse physiological human mucus with diffusivities comparable to those in pure water. This breakthrough offers the prospect of sustained drug delivery at mucosal surfaces, potentially improving the efficacy and reducing side effects of a wide range of therapeutics. The development of MPPs loaded with nucleic acids may also enhance the efficacy of gene therapies. This review highlights the mechanisms by which mucus hinders particle penetration and discusses recent advancements in the design and development of MPPs, which hold promise for improved mucosal drug delivery.