Mechanisms of Ibuprofen Retention and Release in Dual-Responsive P(NIPAM-co-AAc) Nanogels: Coupling of Mesh Sieving and Affinity Switching

Rational design of smart nanogels for drug delivery requires molecular-level understanding of how structural evolution and drug–carrier interactions couple under multiple stimuli. Here, pH/temperature dual-responsive P(NIPAM-co-AAc) nanogels containing 0–20 mol% AAc were investigated by combining all-atom molecular dynamics simulations with in vitro ibuprofen (IBU) release experiments under acidic (pH 2.75) and weakly basic (pH 7.4) conditions at 298 and 310 K. The simulations identified CA-5-L-298 as the most retained system, with the lowest IBU diffusion coefficient (0.92 × 10−7 cm2 s−1) and no dissociated molecules under the adopted criterion, whereas CA-15-H-310 showed the highest diffusivity (8.61 × 10−7 cm2 s−1) and dissociated fraction (22%). Consistently, in the urea-free release experiments, CA-15-H-310 exhibited the highest 24 h cumulative release (69.4%), while CA-5-L-298 remained among the low-release systems (35.9%). Pore analysis, hydrogen-bond statistics, MM/PBSA calculations, and urea-competition experiments together support the view that IBU release is influenced by both mesh steric sieving and polymer–drug affinity switching, and correlation analysis provides quantitative support for linking the MD descriptors with the experimental release behavior. Overall, the simulations reproduce the qualitative trends in the experiments and provide a molecular-level framework for rationalizing the observed release behavior in dual-responsive nanogels.