Thermo-pH dual-responsive nanocarriers enable multiscale-controlled resveratrol release via molecular remodeling and...

Resveratrol (RES) suffers from poor solubility and non-specific distribution, motivating the development of delivery systems with controllable stability and stimulus responsiveness. Here, we construct a hybrid nanocarrier composed of poly(N-isopropylacrylamide) and poly(L-lysine) that exhibits coupled temperature and pH responsiveness. Multiscale molecular simulations in explicit solvent, combined with quantum chemical optimization and free energy analysis, elucidate how external stimuli regulate carrier structure and RES release. At ambient conditions, RES is stably encapsulated within compact polymer clusters through cooperative noncovalent interactions. Elevated temperature induces hydrophobic collapse and structural reorganization, weakening polymer-drug interactions and enabling thermo-responsive release. Under acidic conditions, protonation of lysine segments triggers electrostatic repulsion and cluster dissociation, promoting drug desorption. These coordinated structural and energetic changes define a stimulus-driven "recognition-reconstruction-release" mechanism with tunable and predictable release behavior. Our findings provide molecular-level design principles for programmable nanocarriers targeting polyphenolic therapeutics.