## 4 Bionanosystems
### Bionanosystems for RA
#### 4.1.1. Bionanosystems Based on Organic Carriers  
Most of the examples reported in the literature about the immobilization of RA involve the use of polymer-based micro or nanosystems (Table 1). Generally, natural polymers and biodegradable polymers are selected as the preferred encapsulating materials for applications in the field of skin delivery systems. In fact, these materials are non-toxic, non-reactive in contact with human tissues and can be broken down or metabolized and removed from the body through normal metabolic pathways. Furthermore, their properties depend on the structural features, including composition, molecular weight, and nature of chain end groups. In addition, these polymers can be chemically functionalized to achieve improved properties [15]. Among the different natural polymers used as entrapping materials, chitosan (CS), which is a natural, biodegradable, and hydrophilic polysaccharide, is the one that has been most investigated for encapsulating polyphenols including RA, because it behaves as a stable and protective vehicle to deliver active molecules. Microparticles of CS are very effective as encapsulating systems for bioactive compounds because they are stable in contact with fluids and physiological barriers, protect active compounds from adverse conditions, and can control their release. The properties of the microparticles depend on the molecular weight of the chitosan, the degree of deacetylation, and the mass ratio of chitosan to active ingredient. Many polyphenols are insoluble in water, but through encapsulation in CS microparticles can be delivered topically. In addition, these systems have also been successfully tested for oral and transmucosal delivery of the active ingredient, and in other biomedical, pharmaceutical and food applications, for delivery of natural antioxidants [15; 95; 96; 97; 98]. [PERSON] et al. [91] first encapsulated RA in microparticles of CS and modified-CS (functionalized with carboxylic acid groups that make it more water soluble) prepared by a spray drying process for skin delivery in cosmetic formulations. Spherical RA-loaded microparticles with an average diameter of 4.2 \(\upmu\)m and 7.7 \(\upmu\)m were obtained using CS or modified-CS, respectively. Modified-CS/RA particles showed slower RA release in coconut oil (\(\approx\)75% after 2 h) than in water (pH 5.5) (\(\approx\)100% at 30 min), while CS/RA microparticles revealed a fast release of RA (\(\approx\)90% after 45 min) in both media (Figure 5). This effect was due to the high solubility of the modified-CS in water, which promoted complete disintegration of the microparticles and fast release of RA. Otherwise, modified-CS nanoparticles were less soluble in oil, and consequently RA was trapped longer and released more slowly. Figure 5. SEM micrographs and RA release profile in water and coconut oil of RA-loaded chitosan (**A**) and RA-loaded modified chitosan (**B**) microparticles (adapted from [PERSON] et al. [91], copyright 2016 Elsevier). CS nanoparticles have also been investigated for encapsulating RA or RA-containing extracts [98,99] due to their exceptional ability to release drugs, especially at the mucosal level. Therefore, the encapsulation of antioxidant molecules in CS nanoparticles represents a possible therapy towards the treatment of several chronic diseases characterized by oxidative stress. For example, [PERSON] et al. reported the preparation of CS nanoparticles by ionic gelation of CS and sodium tripolypphosphate in solution and their use as biodegradable mucoadhesive nanocarriers of RA and RA-containing extracts from _Salvia officinalis_ (sage) and _Satureja montana_ (savory) [95,98]. The antioxidant compounds were successfully encapsulated in CS nanoparticles of 200-300 nm, demonstrating the absence of chemical interactions between the antioxidant and CS and showing good release of RA and appreciable antioxidant activity.