## 4 Bionanosystems
### Bionanosystems for RA
#### 4.1.1. Bionanosystems Based on Organic Carriers
However, the inclusion of RA in the emulsion formulation caused a further reduction in \(\beta\)-CA encapsulation efficiency because of the high solubility of RA into the high-pressure mixture of carbon dioxide and organic solvent formed during the emulsion extraction. Among the synthetic polymers used as nanocarriers of RA, [PERSON] et al. [93] prepared RA-loaded polycaprolactone (PCL) microspheres using the emulsion solvent evaporation method. It was demonstrated later that cream formulations containing RA-loaded PCL microspheres have a better long-term stability of RA compared with those containing only RA. Another very interesting method for the encapsulation of plant extracts is the one involving the electrospinningning of poly (3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) solutions containing rosmary extract and green tea extract obtaining ultrathin fibers [117]. Continuous films produced by the annealing of resultant electrospun mats showed antimicrobial and antioxidant activity in both open and closed systems. It was found that the antimicrobial activity was higher in the case of the closed system due to the presence of volatiles stored in the headspace. However, the antioxidant activity of the fibers and films was much lower than that of the neat active substances, which was related to the entrapment and loss during electrospinningning and film processing, and which was also reduced with the passage of days due to the continuous release of the active compounds. Lipid nanotechnology-based systems are another interesting route to encapsulate RA and other plant extracts for drug delivery. For example, RA, due to its physicochemical properties, has low skin penetration efficiency, but its encapsulation in liposomes [118], ethosomes [119] and ultra-deformable liposomes containing fatty acids [120] can increase its transdermal penetration. Liposomes are micro or nanosized spherical vesicles composed of one or more lipid layers containing an aqueous phase. They can also carry both hydrophilic and lipophilic drugs. Due to the presence of phospholipids in their structures, they are similar to biological membranes. Liposomes made of 1:1 Phospholipon 90H and 1,2-dimyristoyl-sn-glycero-3-phospho-(1\({}^{\prime}\)-rac-glycerol) sodium salt loaded with oregano extract containing RA and carvacrol showed an encapsulation efficiency of RA of about 60-70%, and about 80% of RA was released during in vitro test [118]. Figure 8: Chemical structure and digital camera image of RA and poly(RA) particles (adapted from [PERSON] et al. [92], copyright 2019 Elsevier). Ethosomes are vesicular systems composed of phospholipids, ethanol, and a high-water concentration, are very flexible, and can very easily penetrate inside the deep skin layers. Ethosomes prepared using 30% _w/v_ of ethanol and 2% _w/v_ of soya phosphatidylcholine loaded with RA with a particle size of 192 \(\pm\) 1.95 nm, zeta potential of \(-\)32.1 \(\pm\) 2.37 mV, polydispersity index of 0.215 \(\pm\) 0.005 and an encapsulation efficiency of 66 \(\pm\) 1.51% were compared with liposomes made of dipalmitoyl phosphatidylcholine with a particle size of 202 \(\pm\) 1.12 nm, zeta potential of \(-\)11.2 \(\pm\) 1.15 mV, polydispersity index of 0.220 \(\pm\) 0.050 and encapsulation efficiency of 62 \(\pm\) 1.95%. RA-loaded ethosomes and liposomes maintained the antioxidant, anti-collagenase, and anti-elastase effect characteristic of RA. Both ethosomes and liposomes significantly increased RA skin penetration, but ethosomes have been found to be much more efficient than liposomes for delivering the drug to the deeper layer of skin [119]. Finally, ultra-deformable liposomes (ULs) are elastic liposomes generated by the addition of edge activators to liposomes, and those containing fatty acids show high efficiency in skin penetration.