This paper addresses the synthesis and characterization of a novel temperature- and pH-responsive nanogel system based on poly(vinylcaprolactam-co-2-dimethylaminoethyl methacrylate) [P(VCL-co-DMAEMA)] by using a surfactant-free emulsion polymerization procedure for the multiresponsive drug delivery of hydrophobic drugs. The effects of solvent, monomer, pH, and temperature were studied to tailor the average particle hydrodynamic diameters and the polydispersity index of the final particles. According to dynamic light-scattering measurements, the obtained nanogels show a narrow particle-size distribution and their hydrodynamic diameters can be varied from 81 to 368 nm. The nanogels display a re-entrant phase-transition state, and the equilibrium volume swelling ratio of the nanogels decreases drastically down to 47 degrees C and then increases up to 65 degrees C. In addition, the nanogels show pH-dependent behavior. They exhibit a maximum size at pH 5.0. Rhodamine B (RhB) was chosen as a model compound for drug loading and release studies from P(VCL-co-DMAEMA) on the basis of particles in different phosphate buffer solutions at different temperatures. The temperature/pH-dependent cumulative release and ultrasound-enhanced pulsatile release properties were investigated for RhB-loaded nanogels for long-term and one-shot delivery. The nanogels display efficient delivery for both long-term and one-shot delivery systems. We provide here a proof of concept for the novel use of multiresponsive nanogels having an overall size below 200 nm as a cargo system for hydrophobic drugs and for controlled release mediated by temperature/pH and ultrasound.