- Soft nanocomposite hydrogels consisting of thermoresponsive microgels physically entrapped or covalently cross-linked to a non-thermoresponsive hydrogel are synthesized and tested for their capacity to facilitate long-term drug release of a small molecule drug. Copolymer microgels based on N-isopropylacrylamide and acrylic acid were synthesized that exhibited ionic affinity for binding to bupivacaine, a cationic local anesthetic. These microgels were subsequently physically entrapped within an in situ-gelling carbohydrate-based hydrogel network cross-linked via hydrazide-aldehyde chemistry; alternately, hydrazide-functionalized microgels were prepared that covalently cross-linked to the bulk hydrogel phase. Both the overall rate of drug release and the magnitude of the burst release were significantly decreased when microgels were restricted from undergoing a phase transition between the preparation temperature of the nanocomposite (25°C) and the test temperature (37°C), whether deswelling was inhibited by increasing the cross-link density within the microgel itself or by cross-linking the microgel to the bulk hydrogel network. This result facilitates facile tuning of soft nanocomposite drug delivery systems to achieve targeted drug release kinetics.