Eco-Friendly Synthesis, Physicochemical Characterization, and In Vitro Biological Evaluation of Plant-Derived Bioactive-Loaded Chitosan Nanoparticles Supported by Molecular Modeling Studies

Silybum marianum (SM) is a rich source of flavonolignans with promising antioxidant and antidiabetic properties; however, its therapeutic application is limited by poor stability and bioavailability. This study combined experimental and computational approaches to develop and evaluate SM-loaded chitosan nanoparticles (CS–SM nanoparticles). Microwave-assisted extraction followed by LC-MS/MS profiling identified eleven metabolites, including major flavonolignans characteristic of SM. Nanoparticles prepared by ionic gelation exhibited favorable physicochemical properties, including a particle size of 173–189 nm, a polydispersity index of 0.23, a zeta potential of +41.5 mV, an encapsulation efficiency of 98%, and a drug loading capacity of 50%, indicating the formation of a stable colloidal delivery system. CS–SM nanoparticles showed enhanced antioxidant, anti-inflammatory, and α-amylase inhibitory activities compared with crude extracts. The formulation exhibited an α-amylase IC50 value of approximately 0.40 mg/mL and maintained low hemolytic activity, suggesting favorable preliminary biocompatibility. Molecular docking demonstrated favorable interactions of neosilyhermin A, silibinin, and silyhermin with α-amylase and α-glucosidase active sites. Short-timescale molecular dynamics simulations revealed ligand-dependent behavior within the chitosan–TPP matrix, indicating different release tendencies among the investigated flavonolignans. Overall, the results support CS–SM nanoparticles as a promising platform for the delivery of bioactive phytochemicals with antioxidant and antidiabetic potential.