## 3 Some Key Issues on the Use of SLNs and NLCs as Oral Nanovehicles for Nutraceuticals or Bioactives
### Bioactive Absorption and Intestinal Transport  
Before the adsorption though the epithelium cells of the GI tract, the bioactives encapsulated in the mixed micelles (formed after the digestion of lipid particles), or in the intact or partially digested lipid nanoparticles, may be penetrating into the mucous layer covering the surfaces of the enterocytes [25]. If the size of the colloidal structures containing bioactives is too large, they are unable to enter the mucus layer and will remain in the lumen of the GI tract. Here, there are two aspects of adsorption of bioactives that should be considered: (i) absorption of bioactives (solubilized in the mixed micelles); (ii) absorption of lipid nanoparticles [24]. If the lipids in SLNs and NLCs containing bioactives are completely digested by the enzymes during the digestion, before being transported to the adsorption site, only the absorption of bioactives is considered. On the other hand, if the lipid nanoparticles are composed of indigestible lipid components (e.g., essential oils, flavor oils, and fat replacers), or stabilized and coated by indigestible shell layers (e.g., polysaccharides), these particles may be absorbed directly into the systematic system via the portal vein and the intestinal lymph (paracellular or transcellular; see below)--with the caveat that they must penetrate through the mucous layer and be translocated through the epithelium cell layer [24,25,56]. In fact, mixed micelles and other colloidal structures naturally formed during lipid digestion, which usually have sizes \(<100\) nm, can also be considered a kind of lipid nanoparticles. The nanoparticles are taken up by passive diffusion, facilitated diffusion, and active transport across the enterocyte membrane of the GI tract [16]. Figure 5: Schematic illustration for lipid digestion of lipid nanoparticles (SLNs and NLCs) and bioactives (B) solubilization in the small intestine. (Adapted from [25]). The lipid composition, or formulation, of SLNs and NLCs plays a crucial role in the solubilization of their encapsulated bioactives in the mixed micelles (or other colloidal structures), and absorption across the epithelium cell layer. In the cases of certain drugs, drug solubilization or oral bioavailability in the presence of long-chain triglycerides is much more effective than that in the presence of medium-chain lipids [25]. This is largely associated with the facilitated formation of mixed micelles with more hydrophobic fatty acids, MAGs and DAGs incorporated, in the case of long-chain TGs. However, it should be noted that the solubility of poorly water-soluble bioactives (or drugs) is often low in long-chain triglyceride lipids, which may limit their loading capacity in these lipid systems. In general, the micellar solubilization of bioactives, together with free fatty acids, MAGs, or DAGs, greatly enhances the mass transport of these components across the mucous layer. Although there a currently-ongoing debate regarding whether or not micelles are absorbed intact across the unstirred layer in the small intestine, more evidence supports the supposition that free fatty acids (or other components in the mixed micelles) may dissociate in the unstirred layer before partitioning into the enterocyte [25]. These dissociated components are then absorbed across the apical membrane of the enterocyte via passive diffusion or carrier-mediated transport; alternatively, the undissociated micelles may be absorbed by a collisional transfer mechanism, or by a binding (to a transport protein on the apical membrane), followed by vesicular uptake [25]. Following uptake into the enterocytes, free fatty acids, MAGs, or DAGs can be resynthesized to TGs in the smooth endoplasmic reticulum, and further assembled into TG-rich lipoproteins, e.g., chylomicrons and very low-density lipoproteins (VLDL). These lipoproteins are exocytosed from the enterocyte into the lamina propria, which preferentially access the lymphatics (across highly permeable lymphatic endothelium).