Mucosal drug delivery systems offer significant advantages in administering therapeutics directly to mucosal surfaces, enhancing local treatment efficacy while minimizing systemic side effects. However, the mucus layer, which protects these surfaces, poses a substantial barrier to effective drug delivery due to its viscous and adhesive properties that hinder the diffusion of conventional drug formulations. To address this challenge, the development of mucus-penetrating nanoparticles (MPNs) has emerged as a groundbreaking strategy. MPNs are engineered with specific characteristics, such as optimal size, surface charge, and hydrophilicity, enabling them to navigate through the mucus barrier efficiently. These nanoparticles can be modified with surface coatings, like polyethylene glycol (PEG), to reduce mucoadhesion and enhance their diffusivity. Key findings indicate that MPNs significantly improve the bioavailability and therapeutic outcomes of drugs delivered to mucosal surfaces, such as the respiratory, gastrointestinal, reproductive, ocular, and nasal tracts. Clinical studies have demonstrated the potential of MPNs in treating various conditions, including respiratory diseases, gastrointestinal disorders, sexually transmitted infections, and ocular diseases, by providing targeted and sustained drug release. The implications for future research are profound, as ongoing advancements in nanoparticle technology and personalized medicine promise to further enhance the efficiency and specificity of mucosal drug delivery systems. Additionally, addressing the challenges of safety, biocompatibility, regulatory compliance, and large-scale manufacturing will be crucial in translating these innovations from the laboratory to clinical practice. The continued exploration and optimization of MPNs are poised to revolutionize mucosal drug delivery, offering new hope for improved patient outcomes and expanded therapeutic possibilities.