Beyond the barrier: Architectural engineering of electrospun nanofibers for oral, nasal, and vaginal drug delivery.

Transmucosal drug delivery presents a complex interfacial materials challenge where continuous mucus turnover, tight epithelial junctions, and dynamic fluid clearance fundamentally restrict therapeutic efficacy. Electrospun nanofibers have emerged as advanced polymeric platforms capable of overcoming these biological barriers through precision structural engineering and tunable physicochemical properties. This critical review evaluates the solid-state behavior and architectural design of electrospun transmucosal systems, with a specific focus on the dynamic material-mucosa interface. We dissect the mechanistic basis of nanofiber performance, detailing how polymer chemistry, hydration dynamics, and solid-state drug amorphization collectively govern mucoadhesion, mucus penetration, and release kinetics. Furthermore, we critically analyze advanced architectural strategies, including fast-dissolving matrices, sequential-release multilayers, core-shell configurations, and hierarchical nanoparticle-in-nanofiber assemblies, and highlight how the spatial manipulation of polymeric materials dictates functionality across the oral, nasal, and vaginal mucosa. Finally, we address prevailing translational bottlenecks in materials processing, such as the thermodynamic instability of amorphous solid dispersions during scale-up, while outlining future perspectives in stimuli-responsive smart polymers and device-integrated 3D-printed composite scaffolds. Ultimately, this review establishes that the rational engineering of nanofiber morphology, surface chemistry, and solid-state properties is paramount to advancing next-generation mucosal delivery platforms.