Casein-chitosan nanocarriers incorporating Cu/lipase for enzyme-triggered, pH-responsive, and controlled release of ibuprofen.

Due to their biocompatibility and controlled release properties, polymer-based drug delivery systems have been widely studied. However, many of these systems suffer from poor stability and a lack of responsiveness to stimuli. Herein, a novel biocomposite carrier (Cs/Cn-Cu/Lip) was developed by crosslinking chitosan and casein with Cu2+ ions and co-immobilizing lipase, strengthening its affinity for hydrophobic substrates to achieve enzyme-triggered, pH-sensitive ibuprofen (IBU) release. The multifunctional system exhibited high immobilization and encapsulation efficiencies (98.16 % and 97.41 %, respectively) at 25 % drug loading. The particle sizes were approximately 32.4 nm (Cs/Cn-Cu/Lip) and 65.1 nm (IBU/Cs/Cn-Cu/Lip). At pH 1.2, 5.5, 7.4 and 9.5, IBU/Cs/Cn-Cu/Lip released 71.5, 86.7, 85.8 and 84.8 % of the total drug over a period of 48 h, respectively, at 37 °C. Drug release studies at various pH values (1.2, 5.5, 7.4, and 9.5) revealed dynamic, time-dependent, and system-controlled profiles that best fit Gompertz and Logistic kinetic models (R2 > 0.9), exceeding classical diffusion-based release mechanisms. At physiological pH, the carrier system had the highest swelling (22 %) and lowest degradation rate (3 %) at 8 h. The platform maintained lipase bioactivity, contributing to sustained and selective drug release. In vitro cell viability assays demonstrated that the developed nanocarrier maintained high cell viability, with an IC₅₀ of 892.4 μg/mL, indicating its low cytotoxicity and good biocompatibility. Compared to conventional carriers reported in literature, this system shows enhanced stability and controlled release behavior, positioning it as a promising candidate for oral and localized ibuprofen delivery.