## 5 Strategies to Improve the Performance of SLNs and NLCs as Nanovehicles for Nutraceuticals
Furthermore, the residence time of lipid nanoparticles in the gastrointestinal tract is also increased, thanks to the adhesive property of chitosan, which leads to enhanced absorption of the nanoparticles by passive diffusion, and ultimately, improved systemic circulation time and bioavailability of bioactives loaded in these nanoparticles [174]. In an intestinal epithelial cell model (HT-29/B6), it was found that the addition of chitosan (0.005%) induced a fast decrease in transepithelial resistance due to the alteration in intracellular pH caused by the activation of a chloride-bicarbonate exchanger, leading to the opening of tight junction (Tj) proteins [175]. To date, the enhancement of oral intake or bioavailability of bioactives or drugs loaded in SLNs or NLCs by surface coating with chitosan has been reported for curcumin [124], vitamin D [103], silybin [176], docetaxel [177], and cyclosporine A (an extremely hydrophobic cyclic undecapeptide; [178]). The enhancement mechanism was attributed to the enhanced internalization/uptake of the nanoparticles [176; 178], enhanced physical stability in gastrointestinal tract (e.g., for curcumin; [124]) and controlled drug release [174]. Although chitosan coating on the surface of lipid nanoparticles greatly improves the bioavailability of the loaded bioactives, the chitosan-coated lipid nanoparticles are relatively unstable in the intestinal tract, which can possibly lead to the burst release of loaded bioactives and subsequently relatively low bioavailability. This disadvantage has been overcome by using modified chitosan [177; 179; 180; 181]. [PERSON] et al. [177] synthesized hydroxypropyl trimethyl ammonium chloride chitosan (HACC), which showed pH-independent solubility and electro-positivity. They indicated that the SLNs coated with HACC were highly stable in simulated gastric and intestinal fluids, exhibiting much greater oral bioavailability of the loaded docetaxel (compared to free molecules) in rats. [PERSON] and [PERSON] [181] confirmed that, as compared to unmodified chitosan-coated SLNs, N-trimethyl chitosan-coated SLNs exhibited more prolonged stability and controlled drug release in the simulated intestinal fluid, and significantly higher oral bioavailability and brain distribution of loaded curcumin. In this work, it was also confirmed that the burst release of curcumin in the gastric environment was effectively prevented [181]. [PERSON] et al. [180] reported that coating with \(N\), O-carboxymethyl chitosan (NCC) not only protected oxidative and hydrolytic degradation of curcumin loaded in the SLNs upon long-term storage, but also enhanced cytocompatibility with Caco-2 cells. In fact, in an earlier work, it was indicated that the NCC-coated SLNs exhibited suppressed burst release in simulated gastric fluid, but a sustained release in simulated intestinal fluid; NCC-SLN also exhibited enhanced cytotoxicity and cellular uptake on breast cancer cells (MCF-7 cells) [179]. As expected, the lymphatic uptake and oral bioavailability of NCC-SLN were much higher than free curcumin [179]. Improving the Transport across Intestinal Barrier and Target-Delivery of Loaded Nutraceuticals by Surface Modifications with Functional Molecules  
In addition to the enhanced oral bioavailability, surface modification of lipid nanoparticles (SLNs and NLCs) with functional molecules can increase the stability of nutraceuticals loaded in such nanoparticles in systematic circulation [182], transport of drugs across intestinal barriers [183], and their targeted delivery [184]. In addition to the positively charged chitosan, many thiolated polymers with sulfhydryl groups, often termed as thiomers, have been developed to modify the mucoadhesive properties of lipid nanoparticles [184]. Thiomers can form disulfide bonds between sulfhydryl  
Figure 8: Schematic representation of several types of surface-modified SLNs.