Electrospraying is renowned for its simplicity and versatility, and which can effectively produce particles with well-controlled size, size distribution, particle shape, morphology and microstructure at the nano/microscale. In this study, coaxial electrospraying was used to investigate its feasibility for preparing nanoparticles made up of nanocrystals encapsulated within a polymer shell. Firstly, aqueous nanosuspensions of darunavir were prepared by wet media milling. Then the nanosuspension and solutions of an enteric polymer, Eudragit L100, were used as the inner/core liquid and outer/shell liquid in a coaxial electrospraying setup, respectively. As long as a sufficiently high voltage was applied, a stable Taylor cone-jet mode was obtained to produce very fine core-shell structure nanoparticles with high darunavir encapsulation efficiency of approximately 90%. The influence of the starting nanosuspension and the flow rates on the characteristics of the final electrosprayed particles was also evaluated. Using an optimized nanosuspension with reasonable size, size distribution and flow rates, the enteric coating layer reduced the percentage of DRV release in acidic medium in the in vitro dissolution test to ca. 20%. This study indicates that coaxial electrospraying is a potential and unique technique for encapsulating drug nanocrystals within a polymeric shell.