The loading properties of ibuprofen (IBU) were investigated using poly(N-isopropylacrylamide-co-acrylic acid) P(NIPAM-co-AA) copolymer nanoparticles as a carrier. Subsequently, the sensitivity of controlled release performance during changing external conditions and composition of copolymer were evaluated in detail. The results showed that the introduction of AA chains into PNIPAM framework enhanced the loading of IBU and the maximum loading capability of P(NIPAM-co-AA)-3 reached up to 7.9 wt%. The release behaviors of IBU-loaded copolymers exhibited high responsiveness to temperature and pH values. For example, P(NIPAM-co-AA)-10 exhibited a high cumulative release amount of 83.2% at 37 A degrees C/pH 7.4, and a significant decrease in the release amount of 32.2% at 37 A degrees C/pH 2.0. The influence of various amounts of acrylic acid (AA) and salt effect (ionic strength) on the swelling behaviors were demonstrated via dynamic light scattering method. Their microstructures and morphologies were characterized using scanning electron microscopy (SEM), transmission electron microscopy (TEM) and small-angle X-ray scattering (SAXS) techniques, which confirmed the presence of fractal structures with D-m (2.65-2.87) or D-s (2.0-2.33). These results further suggested that the structural evolution of P(NIPAM-co-AA) copolymer with increasing AA content had occurred from loose networks to dense aggregates with statistical self-similarity. The IBU-release mechanism was proposed, whereas the IBU diffusion contribution from P(NIPAM-co-AA) was thoroughly elucidated using three empirical equations, namely Korsmeyer-Peppas model, modified Korsmeyer-Peppas model and Higuchi model, respectively. The obtained results demonstrated that the release procedure of P(NIPAM-co-AA) was driven by typical non-Fickian diffusion mechanism in the basic medium, while in acid medium a two-stage release mechanism was observed due to their aggregation behaviors.