## 3 Some Key Issues on the Use of SLNs and NLCs as Oral Nanovehicles for Nutraceuticals or Bioactives
### Lipid Digestion and Bioactive Solubilization  
A nanoparticle in food, after ingestion, experiences different stresses (e.g., pH, ionic strength, temperature, digestion fluids, mechanical mixing, and action of enzymes) of gastrointestinal (GI) processes, with respect to mouth, stomach, small intestine, and colon. Changes in the size and interfacial characteristics (e.g., \(\zeta\)-potential) of the nanoparticle may occur as it passes through different stages of the GI tract; these are highly dependent on the type of applied emulsifiers [24]. For lipid nanoparticles stabilized by Tween 20, as frequently observed in SLNs and NLCs, their particle size and \(\zeta\)-potential slightly change after the mouth and stomach stages of simulated digestion, but small-intestine digestion results in a significant increase in particle size (largely as a result of droplet flocculation and coalescence), and magnitude of \(\zeta\)-potential. This implies that most nanoparticles of SLNs or NLCs may exhibit a high degree og stability against gastric digestion, e.g., strong acid (pH 1-3), high ionic strength, and high enzyme activity (e.g., gastric lipases), as was confirmed in a simulated gastric and intestinal digestion work for trimyristin nanoparticles [52]. Upon entering the small intestine, the acidic gastric digest (of lipid nanoparticles) is mixed with the alkaline small intestinal fluids from gall bladder and pancreas, which contain bile acids (BA), phospholipids (PL), pancreatic lipase and co-lipase, and salts. As a result, the pH of the mixture increases up to around neutral. It should be mentioned that the secretion of endogenous biliary lipids (BS, PL, and cholesterol) from the gall bladder is significantly enhanced by the presence of exogenous lipids in the small intestine. In this regard, long-chain fatty acids seem to be much more effective in stimulating the secretion of bile by the gall bladder [25]. In the small intestine, pancreatic lipase, together with its co-factor co-lipase, is adsorbed at the interface of lipid nanoparticles (SLNs or NLCs), and catalyzes TG to release diglycerides, monoglycerides, and fatty acids [25]. If exogenous PL is present, e.g., as emulsifiers for lipid nanoparticles, the hydrolysis of PL by pancreatic phospholipase A\({}_{2}\) also occurs in the small intestine, yielding lysophophatidylcholine and fatty acids. Then, in the presence of endogenous BS and PL at enhanced concentrations, the products of lipid digestion (monoglycerides, fatty acids and lysophospholipids) are incorporated into a series of colloidal nanoarchitectures with a variety of structures, such as multilamellar and unilamellar vesicles, mixed micelles, and micelles [25]. The bioactives released from the lipid nanoparticles as a result of lipid hydrolysis can be favorably transferred into the interior of these nanoarchitectures, thus causing significantly improved solubility of these bioactives in the small intestine fluid. The detailed description for the process of lipid digestion (of SLNs or NLCs) and bioactive solubilization in the small intestine is illustrated in Figure 5.  
The bioactive solubilization capacity of these colloidal architectures significantly increases upon addition of exogenous lipids (from formulation or foods) and is dependent on the nature of the digestion products (e.g., fatty acid chain length) and the structural characteristics of the colloidal architectures [25]. Thus, it can be reasonably expected that the bioaccessibility of bioactives encapsulated in the lipid nanoparticles (SLNs or NLCs), which is defined as the fraction of bioactives released from their lipid matrix and solubilized within the GI fluid that can be adsorbed [53], varies significantly with differences in the composition, concentration, and nature of lipids in their lipid matrix. For example, [PERSON] et al. [52] observed that the transfer of curcuminoids in the SLNs into the simulated GI fluid was mainly triggered by the lipid degradation and not by the bioactive release.