Background: The objective of this investigation was to develop a new type of solid dispersion in the form of core-sheath nanofibers using coaxial electrospinning for poorly water-soluble drugs. Different functional ingredients can be placed in various parts of core-sheath nanofibers to improve synergistically the dissolution and permeation properties of encapsulated drugs and to enable drugs to exert their actions. Methods: Using acyclovir as a model drug, polyvinylpyrrolidone as the hydrophilic filament-forming polymer matrix, sodium dodecyl sulfate as a transmembrane enhancer, and sucralose as a sweetener, core-sheath nanofibers were successfully prepared, with the sheath part consisting of polyvinylpyrrolidone, sodium dodecyl sulfate, and sucralose, and the core part composed of polyvinylpyrrolidone and acyclovir. Results: The core-sheath nanofibers had an average diameter of 410 +/- 94 nm with a uniform structure and smooth surface. Differential scanning calorimetry and x-ray diffraction results demonstrated that acyclovir, sodium dodecyl sulfate, and sucralose were well distributed in the polyvinylpyrrolidone matrix in an amorphous state due to favoring of second-order interactions. In vitro dissolution and permeation studies showed that the core-sheath nanofiber solid dispersions could rapidly release acyclovir within one minute, with an over six-fold increased permeation rate across the sublingual mucosa compared with that of crude acyclovir particles. Conclusion: The study reported here provides an example of the systematic design, preparation, characterization, and application of a novel type of solid dispersion consisting of multiple components and structural characteristics.