Silk fibroin (SF), a FDA-approved natural protein, is renowned for its great biocompatibility, biodegradability, and mechanical properties. SF-based nanoparticles provide new options for drug delivery with their tunable drug loading and release properties. To take advantage of the features of carrier polymers, we present a one-step electrospraying method that combines SF, polyvinyl alcohol (PVA) and therapeutic drugs without an emulsion process. A distinct core-shell structure was obtained with the PVA core and silk shell after the system was properly set up. The model drug, doxorubicin, was encapsulated in the core with a greater than 90% drug encapsulation efficiency. Controllable drug release profiles were achieved by alternating the PVA/SF ratio. Although the initial burst release of the drug was minimized by the SF coating, a large number of drug molecules remained entrapped by the carrier polymers. To promote and trigger drug release on demand, low intensity focused ultrasound (US) was applied. The US was especially advantageous for accelerating the drug diffusion and release. The apoptotic activity of MDA-MB-231 cells incubated with drug-loaded nanoparticles was found to increase with time. In addition, we also observed PVA/SF nanoparticles that could elicit a drug release in response to pH.