A modified coaxial electrospraying process, which was characterized by the use of pure solvent as a sheath working fluid, was developed for the continuous and robust generation of medicated nanoparticles. Tamoxifen citrate (TAM) was encapsulated in zein, a plant protein. The influences of the key parameter shell-to-core fluid flow rate on the electrospraying processes and on the resulting protein-based composite particles were investigated in detail. Scanning electron microscopy images revealed that compared with particles prepared via the traditional single-fluid process, TAM-loaded zein particles prepared via the modified coaxial process were rounder with smaller diameters, narrower smaller size distribution, and more compact inner structures. Owing to the reinforced secondary interactions between TAM and zein, all the particles were similarly amorphous composites, as verified by their X-ray patterns and attenuated total reflectance-Fourier transform infrared spectra. The medicated nanoparticles synthesized via the coaxial process exhibited a better drug sustained-release profile than those synthesized via the traditional single-fluid process, with a smaller initial burst release, longer release period, and shorter tailing-off stage. The microformation mechanisms of the electrosprayed particles and their drug sustained-release mechanisms were suggested. By altering the traditional concept of electrospraying, the modified coaxial electrospraying method developed in this study provides a powerful new process for the generation of nanoparticles with novel structures and functions.