Solid nanoparticle-lipid hybrids have been engineered by using spray drying to assemble monodisperse hydrophilic silica nanoparticles and submicron lipid (triglyceride) emulsions together into composite microparticles, which have specific activity toward enzymes. The influence of silica particle size (100-1000 nm) and emulsifier type (anionic and cationic) on the three-dimensional structure of the composite particles was investigated. The nanostructure of the hybrid particles, which is controlled by the size of the voids between the closely packed silica particles, plays a critical role in lipase action and hence lipid digestion kinetics. Confining lipid droplets within the nanostructured silica aggregates led to 2- to 15-fold enhanced rate of lipolysis in comparison with dispersed coarse oil droplets. The composite particles were tailored to enhance, retain or sustain the lipolysis kinetics of submicron lipid emulsions. The presence of repulsive nanoparticle-droplet interactions favored aqueous redispersion and fast lipolysis of the hybrid composite materials, while attractive interactions hindered redispersion and delayed lipolysis of the confined lipid droplets. Such hybrid nanomaterials can be exploited to control the gastrointestinal enzymatic action and promisingly form the basis for the next generation of foods and medicines.