Hybrid silica/Eudragit®RS microparticles (MPs) with a core-shell structure have been successfully synthesized in a single step via a microfluidic jet spray dryer. The precursor consisted of hydrolysed tetraethyl orthosilicate (TEOS) sol in acidic condition mixed with a diluted Eudragit®RS aqueous dispersion in different mass proportions. The spray dryer reproducibly produced uniform MPs (i.e. particle size, morphology, and structure) within the batches. The core of the particles was silica, while the shell was composed of Eudragit®RS component mixed with a fraction of silica. The mechanism of such structure formation was proposed, by applying the Stokes-Einstein equation to compare the molecular diffusivities of different components. During the drying process, the slower molecular diffusivity of Eudragit®RS compared to silica due to the larger hydrodynamic radius, consequently resulted in prior precipitation of Eudragit®RS to silica. The direct correlations between the precursor composition, i.e. mass ratio between silica and Eudragit®RS, with the microparticle size, morphology and shell thickness were also discussed. Such core-shell structured particles have great potentials as hybrid carriers for drug delivery and controlled release applications. This work illustrated that core-shell particles can be achieved in a single step drying, instead of via wet synthesis route that usually involved complex reactions, purification step, large amount of chemical waste, and undesirable use of organic solvent.