**4. Mechanism of lipid nanoparticles**

Regarding the typical triglyceride-based lipid nano-particles will undergo the same digestive processes as lipids consumed through food after being administered orally. Still, mechanism of oral bioavailability has now no longer been defined but some of the additives are standard for know-how the enhancement of absorption. Surface area, smaller particle size and morphology are extra suitable traits for oral absorption. Since lipids are regarded to improve oral absorption of drug and they can be prepared with less particle size, it has been concluded that this carrier system must use lipids as the excipient for greater and steady absorption through gastrointestinal pathway [55]. Additionally, solid-lipid nanoparticles (SLNs) surface area, interaction with epithelial membranes and bio adhesion to the GI wall appear to extend their absorption in the GIT, which probably improves oral absorption. There are three basic mechanisms for oral administration of lipids, lipophilic excipients and lipid-based formulation for increased absorption [56],


According to a claim that lipid nanoparticles have adhesive characteristics that allow them to adhere to the surface of enterocytes in the stomach and immediately release drugs for absorption into the cells. Parallel to this, SLN contributes significantly to the formation of micelles in the oral uptake by causing the release of bile salts and lipase/co-lipase, Additionally, the bile salts and micelles interact to form mixed micelles that facilitate the absorption of these colloidal species by enterocytes, which transport drugs inside cells, these mechanisms have been called the "Trojan horse" effect [57]. Micelles are created after absorption and present in the enterocyte, where they are re-esterified via the monoacyl glycerol or phosphatidic acid route to become chylomicrons and maintained by phospholipids. The penetration of mucus and unstirred water layer, however, is what restricts the rate of digestion. Following formation, the chylomicrons are subjected to the lymphatic transport system via mesenteric lymph before being drained by the thoracic duct [58, 59].

Following oral administration, several techniques for drug transport into the lymphatic system have been reported. These Peyer's patches contained M cells that are used for vaccine distribution through the transcellular and paracellular mechanisms [55], as well as therapeutic drugs and nanocarriers. The transcellular approach is the most fundamental technique for lipid-based carriers to be absorbed. Enterocytes are promoted to generate chylomicron when drug is delivered using lipid-based transporters, which further emulsify and incorporate the lipophilic drug molecules into the nonpolar core. This stimulates the intestinal lymphatics to absorb drugs that are just slightly water soluble.

Additionally, lipid-based carriers can enhance intestinal lymphatic lipid flux and lipoprotein production, both of which are regulated by the physiochemical characteristics of lipids and the presence of stabilizer. Lipid-based transcellular routes are additional. There are various transcellular mechanisms through which lipid-based drug delivery systems are transported into enterocytes, including macro-pinocytosis, caveolae-mediated, clathrin-mediated and clathrin and caveolae-independent endocytosis [60].

Griffin and O'Driscoll gave explanations for how the lipid-based formulations improved the oral absorption of lipophilic drugs specifically for peptide and proteinlike drugs, in addition, to improving intestinal lymphatic transport and drug solubilization. These enclosed increased intestinal membrane permeability, fluidization of the intestinal membranes, reduce the enzymatic degradation, alteration of TJs, generation of lipid-protein interactions and alteration of enterocyte-based efflux and metabolic activities are some of these [61].

In addition to the above-mentioned factors, lipid-based formulations stimulate prolonged gastric emptying, which prolongs the stomach's time in the stomach and increases the rates at which drug molecules dissolve at the absorptive site, hence improving drug absorption [62]. As a result, lipid-based nanoparticles increase the oral bioavailability of lipophilic drugs through bio-adhesion mechanisms in addition to endogenous lipid absorption pathways, which include absorption through M cells of Peyer's patches, solubilization, permeability across the enterocyte, increased paracellular and transcellular transport, controlled drug release, delayed gastric emptying time, stimulation of lymphatic transport, avoidance of intestinal first-pass metabolism, etc.

The review demonstrated that due to the unique characteristics of lipid nanoparticles and its components (wide variety of lipid constituents such as P-gp inhibitor, permeability enhancer, endogenous solubilizing components, etc.) multiple mechanisms for absorption and permeation, no toxicity and its formulation opportunities including avoidance of organic solvents during production of complex and challenging formulation strategy for drugs that, when taken orally have poor water solubility [63], Drug (lipid-nano formulation) may be eliminated from the body after oral administration as a result of its lipophilicity, which is directly affected to the bioavailability of drug molecules and lipid nanoparticles. Changes in the components of lipids may affect the bioavailability of bioactive characteristics, including, such of those vaccines. However, adding the surface of lipid nanoparticles with a surface-active substance like PEG prolongs their stay in the bloodstream while preventing phagocytosis uptake.
