## 3 Some Key Issues on the Use of SLNs and NLCs as Oral Nanovehicles for Nutraceuticals or Bioactives
### Poorly Soluble Bioactive Compounds
#### 4.2.2 Polyphenols  
Polyphenols are a kind of phytochemical, found in a wide range of plant-based foods and beverages, including tea, apples, citrus fruit, berries, and coffee. They have been well documented as beneficial for modern human nutrition and health [147; 148]. Substantial epidemiological evidence supports close relationships between the administration of polyphenol-rich vegetable and fruits and reduced risks of many chronic diseases, e.g., stroke, myocardial infarction, diabetes, cancers, and hyperglycemia [147; 148]. The major polyphenols from dietary plants include flavonoids (e.g., quercetin), flavon-3-ols (e.g., catechin and epicatechin), flavanones (e.g., hesperetin), flavones (apigenin and luteolin), isoflav, anthocyanins, proanthocyanidins, hydroxycinnamates, and phenolic acids [147]. Many polyphenols, e.g., resveratrol, are extremely poorly soluble in water, and susceptible to degradation upon storage or when exposed to lights; they may also undergo extensive first-pass metabolism, resulting in low bioavailability [149]. For example, the oral absorption of resveratrol in humans is high (~75%), primarily through transepithelial diffusion, but its bioavailability is less than 1%, due to extensive metabolism in the intestine and liver [149]. Other works have confirmed that lipid nanoparticles (SLNs and NLCs) can perform as promising and effective delivery carriers for improving water solubility,stability and bioavailability of such poorly soluble polyphenols, e.g., quercetin [150; 151; 152; 153; 154], resveratrol [155], or morin [156]. Similar to curcuminoids, poorly soluble polyphenols can be incorporated into the lipid matrices of SLNs or NLCs through direct solubilization in melted lipids [150; 151; 152], or initial solubilization in organic solvents prior to mixing with melted lipids [153; 154; 155; 156]. Quercetin is one of the most important and investigated flavonoids to be encapsulated in lipid nanoparticles for improved bioavailability and benefiting effects. In an investigation of the structure-antioxidant activity relationships of several flavonoids (myricetin, quercetin, kaempfer, luteolin, apigenin, and chrysin), quercetin (having four hydroxyl groups) was demonstrated to exhibit the highest activity [157]. Furthermore, it has been documented that quercetin is a more potent antioxidant and radical scavenger than vitamin C, vitamin E, and \(\beta\)-carotene [158]. In order to improve the therapeutic efficacy of this flavonoid in Alzheimer's disease by utilizing its outstanding antioxidant potential, [PERSON] et al. [152] developed a Tween 80-stabilized SLN, fabricated using a microemulsion template method, with quercetin directly incorporated in the melted lipids. It exhibited a high entrapment efficiency of around 86%, and demonstrated that, through intravenous administration, the as-fabricated quercetin-loaded SLNs could effectively cross the BBB, and were successfully target-delivered to the brains of rats. [PERSON] et al. [150] compared the effectiveness of using SLNs, NLCs, and lipid nanoemulsions (LNE) as delivery nanovhelics for quercetin, indicating that all the test nanovhelics had a high EE of quercetin (\(>\)90%) and were stable in simulated stomach conditions. The maximum bioaccessibility was observed with NLC and LNE (\(\sim\)60%), compared to SLN (\(\sim\)35%) and free quercetin solutions (\(\sim\)7%). They also confirmed that both the encapsulated quercetin in the SLN and NLC exhibited a controlled release behavior in simulated intestinal fluid [150]. The much greater bioaccessibility of quercetin in SLN (or NLC), as compared to free quercetin, in fact, was well in agreement with the much greater bioavailability of quercetin encapsulated in SLNs (relative to free quercetin suspension), as confirmed in an earlier work by [PERSON] et al. [153]. In situ perfusion experiments in rats indicated that most of the encapsulated quercetin in the SLNs was mainly absorbed in the ileum and colon [153].