## 5 Strategies to Improve the Performance of SLNs and NLCs as Nanovehicles for Nutraceuticals
groups on thiomers and cysteine, rich on glycoproteins, in the mucus layer of the gastrointestinal tract, thus improving the adhesion properties, prolonging the retention time in the gastrointestinal tract, and enhancing the penetration and absorption of drugs [185; 186]. Furthermore, due to the interaction between thiol groups and the transmembrane region of the efflux pump, thiomers can inhibit P-glycoprotein activity in small intestinal epithelial cells, thereby enhancing drug absorption efficiency [187]. Cysteine and its derivatives are common modifiers of thiolation. [PERSON] et al. [185] reported that the surface modification of docetaxel-loaded NLCs with cysteine significantly improved their adhesion properties and absorption efficiency, and the oral bioavailability levels of docetaxel loaded in the cysteine-functionalized NLCs were 12.3-fold and 1.64-fold higher than free docetaxel and unfunctionalized NLCs, respectively. [PERSON] and colleagues [188] used N-acetyl-L-cysteine to modify curcumin-loaded NLCs, and showed that the oral bioavailability of curcumin in rats was positively correlated with the degree of surface modification of NLCs, and the bioavailability of curcumin in the optimal group was 499.45-fold and 116.89-fold higher than free curcumin and curcumin loaded in unmodified NLCs, respectively. Cell-penetrating peptides are a class of small molecule peptides with transmembrane transport ability, generally consisting of 5-30 amino acid residues. They are rich in basic amino acids, polycationic and amphipathic [189]. These peptides are electrostatically interacted with, or covalently bound to, a variety of exogenous substances, such as peptides, oligonucleotides, liposomes, or SLNs. It is generally recognized that these peptide complexes or conjugates enter cells by two mechanisms of membrane penetration: non-energy-dependent direct penetration and energy-dependent endocytosis, though the mechanism of membrane penetration remains controversial [190]. [PERSON] et al. [183] prepared two cell-penetrating peptide-modified SLNs loaded with salmon calcitonin, which had a greater ability to promote cellular internalization and mucosal penetration than unmodified SLNs. The mechanism of action was mainly active transport via latticin and fossa-dependent endocytosis. Cell-penetrating peptide modification of SLNs enhanced the oral bioavailability of the active ingredient [183]. [PERSON] et al. [184] reported that the surface modification of NLCs with lactoferrin produced novel low-density lipoprotein (LDL)-mimic NLCs which could perform as brain-targeted delivery nanocarriers for curcumin. They demonstrated that the modification greatly improved the uptake of surface-modified NLCs in the brain capillary endothelial cells; the as-fabricated LNCs effectively permeated brain blood barriers (BBB) and preferentially accumulated in the brain (2.78 times greater than those loaded in the unmodified NLC) [184]. A variety of specific receptors exist on cells, and the transport of active molecules in lipid nanoparticles can be enhanced by surface modification with specific ligands. Considering that bile acid transporters are available on intestinal epithelial cells, [PERSON] and colleagues [191] demonstrated that the surface modification of NLCs with taurocholic acid remarkably improved the intestinal absorption and oral bioavailability of curcumin loaded in the NLCs. The AUC of curcumin, after oral administration in rats, was 5-15-fold higher than that of unmodified NLCs at different levels of modification, suggesting that the addition of taurocholic acid ligands to NLCs promoted curcumin absorption [191]. The folate receptor is a ubiquitous receptor on cells, but it is overexpressed in a variety of solid tumor cells. The use of folic acid for targeted delivery of antitumor drugs has been heavily investigated for the ability of folic acid-bound molecules or delivery vehicles to enter cells via folic acid receptor-mediated endocytosis [192].