Solid Lipid–Threshold Guided Chitosan Coating of NLCs for Improved Gastrointestinal Stability and Curcumin Bioavailability

Chitosan-coated nanostructured lipid carriers (CS-NLCs) were engineered to overcome the gastrointestinal instability and limited absorption of glycerol distearate (GDS)/medium-chain triglyceride (MCT)-based NLCs. Using a dropwise coating method, we systematically evaluated the impact of chitosan coating on digestive stability and intestinal permeability through in vitro digestion models, Ussing chamber assays, and confocal laser scanning microscopy (CLSM). The results indicate that Chitosan coating improved NLCs’ storage stability (except G2M8 formulation). CS-NLCs exhibited more complete digestion (the maximum fatty acid released within 20   minutes versus 30   minutes for uncoated NLCs), with Turbiscan analysis demonstrating an increase in initial digestion rate compared to uncoated NLCs, though chitosan-induced flocculation reduced small intestinal permeability (52% lower apparent permeability coefficient in Ussing chambers). CLSM imaging identified a critical solid lipid threshold (>50%) for chitosan-mediated adhesion enhancement, with 80% solid lipid CS-NLCs showing 1.6-fold higher mucus adhesion due to incomplete chitosan degradation and increased particle size (from 747   nm to 16μm). Pharmacokinetic studies in rats confirmed that CS-NLCs with >50% solid lipid achieved 1.8-fold higher curcumin bioavailability versus uncoated counterparts. This study highlights the critical role of chitosan coating in optimizing the bioavailability of lipid-based nutraceuticals in the gastrointestinal tract.