Casein Micelles Reinforced With Hollow <scp>CuS</scp> Nanoparticles: A Sustained and <scp>pH</scp> / <scp>NIR</scp> Dual‐Responsive Drug Delivery Platform

ABSTRACT Casein‐based nanocarriers have demonstrated significant potential in drug delivery due to their excellent biocompatibility, amphiphilic nature, and pH responsiveness. However, casein‐based drug carriers suffer from the problems of single intelligent response and poor controllability of drug release. In this study, casein was combined with hollow copper sulfide (CuS) nanoparticles with near‐infrared (NIR) responsiveness through electrostatic self‐assembly interaction to generate CuS@casein micelles (CuS@CM) with sustained and pH/NIR dual‐responsive drug release properties. The strong negative charge of casein and the hollow structure of CuS ensure a high doxorubicin (DOX) loading efficiency (96.84%) of CuS@CM. Ca 2+ is bound with casein to form inter‐casein calcium bridges, thereby providing significant sustained release properties for CuS@CM. The charge inversion property of casein at different pH values and excellent NIR responsiveness of hollow CuS nanoparticles endows CuS@CM with superior pH/NIR dual‐responsive drug release performance. In vitro cell viability results demonstrated that the pH/NIR dual‐responsiveness of CuS@CM‐DOX, as well as its excellent tumor cellular uptake capability, could effectively induce tumor cell death. Overall, this study generates a novel casein‐based nanocarrier with sustained and pH/NIR dual‐responsive drug delivery properties, which has potential application in the field of tumor‐targeted drug delivery.