A hybrid nanocomposite comprised by porous silicon nanoparticles and a stimuli responsive polymeric material, polyethylene glycol-block-poly(L-histidine), is spontaneously formed by nanoprecipitation in a flow-focusing microfluidic chip. The nanocomposite presents a novel hybrid compound micelle structure with a great robustness for therapeutic applications. Therefore, the nanocomposite is developed and tested as a "smart" multistage drug delivery system (MDDS) in response to some of the current problems that cancer treatment presents. Based on the stimuli-responsive behavior of the nanocomposite, a chemotherapeutic agent is successfully loaded into the nanosystem and released upon changes in the pH-values. The nanocomposite demonstrates enhanced stability in plasma, narrow size distribution, improved surface smoothness, and high cytocompatibility. Furthermore, the nanocomposite presents reduced nanoparticle internalization by phagocytic macrophage cells and pH-dependent cell growth inhibition capacity. Overall, the developed hybrid nanocomposite shows very promising features for its further development as a "smart" pH-responsive MDDS.