We present a microfluidic method to direct the self-assembly of temperature-sensitive liposome-hydrogel hybrid nanoparticles. Our approach yields nanoparticles with structural properties and highly monodisperse size distributions precisely controlled across a broad range relevant to the targeted delivery and controlled release of encapsulated therapeutic agents. We used microfluidic hydrodynamic focusing to control the convective-diffusive mixing of two miscible nanoparticle precursor solutions (a DPPC:cholesterol:DCP phospholipid formulation in isopropanol and a photopolymerizable N-isopropylacrylamide mixture in aqueous butler) to form nanoscale lipid vesicles with encapsulated hydrogel precursors. These precursor nanoparticles were collected off-chip and were irradiated with ultraviolet (UV) light in bulk to polymerize the nanoparticle interiors into hydrogel cores. Multiangle laser light scattering in conjunction with asymmetric flow field-flow fractionation was used to characterize nanoparticle size distributions, which spanned the approximate to 150 to approximate to 300 nm diameter range as controlled by microfluidic mixing conditions, with a polydispersity of approximate to 3% to approximate to 5% (relative standard deviation). Transmission electron microscopy was then used to confirm the spherical shape and core-shell composition of the hybrid nanoparticles. This method may be extended to the directed self-assembly of other similar cross-linked hybrid nanoparticle systems with engineered size/structure-function relationships for practical use in healthcare and life science applications.