It has been commonly discovered that reducing particle size always accompanies with undesirable deterioration of drug encapsulation efficiency in double emulsion based techniques. However, a clear optimization strategy for process variables to minimize this negative impact has been rarely reported. To fill this gap, we have successfully developed an optimization strategy for silica xerogel/polymer composite nanoparticles prepared by our recently developed gelation-emulsion method. To develop this strategy, interactive effects of multiple process variables were investigated through a four-factor three-level experimental design by considering all screened dominant process variables influencing particle size and encapsulation efficiency, including sonication time of second emulsion (t(2)), sonication power of the second emulsion (P-2), total volume of the second emulsion (V-2) and volume ratio of aqueous phase and primary emulsion (r). The optimization strategy for fabricating the target particle size with optimal encapsulation efficiency was designed by adjusting the process variables in the order of r, V-2, t(2), and P-2 With this strategy, conspicuous enhancement of the encapsulation efficiency (e.g., from 27 to 63% for a particle size of 211 nm) and significant increment of the feasible size range through our novel fabrication method from 192-569 nm to 90-914 nm have been achieved in this study. POLYM. ENG. SCI., 2017. (c) 2017 Society of Plastics Engineers