**2.1 Polymeric nanocapsules**

Polymeric nanoparticles are colloidal and are prepared from degradable/nondegradable hydrophilic/hydrophobic natural/synthetic polymers. Natural polymers, such as polysaccharides (hyaluronic acid, starch, maltodextrins, chitosan, cyclodextrins, alginate, carrageenan, gums, and agar) or proteins (gliadin, vicilin, legumin, casein, gelatines, and albumin) are not usually used alone due to the variability of their purity. Nanocapsules based on saccharides (glyco nanocapsules) are very interesting for bioapplications. The synthetic polymers usually used are poly(lactic-co-glycolic) acid (PLGA), poly(lactic acid) (PLA), poly(ε-caprolactone) (PCL), polyanionic cellulose (PAC), poly(D,L-glycolide) (PLG), polyethylene glycol (PEG), and poly-cyanoacrylate (PCA) [1, 7–10]. Polymeric nanoparticles made from natural or synthetic polymers are easy to modify superficially and are, in general, stable. Their features can be tuned to achieve better bioavailability and a controlled drug release in specific locations. Biodegradable polymers have been widely used for the preparation of systems to control drug release, which can stabilize certain labile molecules, such as proteins, peptides, or DNA, and can also be used for site-specific drug targeting. The preparation of biodegradable polymeric nanoparticles for application in tissue engineering is also pursued [1]. As they are biodegradable, they can remain for days or even weeks and release the drug in the target during that time. PLA and PLGA have proved to be effective with intracellular drugs. PLGA is usually combined with PEG, as PEGylation increases solubility and stability in water, reduces intramolecular aggregation, decreases immunogenicity, and prolongs the permanence of the drug in the systemic circulation [1, 7]. As an example, a recent review (in press) shows a representation of some modifications on the surface of polymeric nanocapsules (polymer-coating; PEGcoating; layer-by-layer; polymersomes; and inner portion—hollow-core) [5].

Chitosan, alginate, and cellulose are the natural polymers most widely used in medicine due to their geometry, their large specific surface, their mechanic and barrier properties, their low toxicity, and their biodegradability and biocompatibility [11, 12]. Chitosan is a biodegradable cationic polymer that can be obtained from crustaceans, insects, mollusks, and fungi. Usually, it is obtained for industrial use from crustacean exoskeletons, mainly from the waste products of the fishing industry. The properties that make it interesting for use are its molecular weight, deacetylation degree, solubility, biocompatibility, and bioadhesion. It presents antimicrobial activity against fungi, viruses, and bacteria. The application of nanospheres and nanocapsules of chitosan in cartilage and bone regenerative medicine is currently being studied due to the aforementioned properties [13]. The polysaccharide alginate is used in therapeutics because of its biocompatibility, low immunogenicity, and ability to gelation. Moreover, it is a pH-sensitive polymer that can be used to prevent drug release in an acid medium, such as gastric juice, when it is necessary for the active to be released in an alkaline medium (e.g., in oral administration of intestinal targeted drug delivery) [6]. In Ref. [14], nanospheres with alginate and chitosan loaded with the insecticide captan hydrochloride are obtained. Cellulose can be extracted from different natural sources. It is highly abundant, and the development of cellulosebased systems for drug release applicable to cancer therapy has increased enormously in the last decade [11].

Proteins, such as albumin, which are biocompatible and able to be tuned, are also used as polymeric shells for nanocapsules. Albumin is water-soluble and biodegradable. Apart from controlling drug release rate, albumin can reduce the nanosystem immunogenicity, and it can be useful as a drug targeting vector [6].

In Ref. [15] several polymeric systems are described, containing hybrid lecithin/ chitosan nanoparticles, PCL nanocapsules stabilized with the non-ionic surfactant polysorbate 80, and polymeric PCL nanocapsules stabilized with a polysaccharidebased surfactant, that is, sodium caproyl hyaluronate. These three systems present interesting physicochemical and structural properties from the biopharmaceutical viewpoint for nasal and nose-to-brain delivery—biocompatibility, drug release, mucoadhesion, and permeation across the nasal mucous membrane. All three systems improved the transport of the hypolipidemic drug simvastatin through the epithelial barrier of the nasal cavity, compared to the traditional formulation.

According to reference [7], polymeric nanoparticles present several disadvantages, such as toxicity, presence of organic solvent residues, inadequate encapsulation of hydrophilic drugs, losses, difficulty of large-scale production, and storage and sterilization issues. Besides, the organism may receive them as strange particles. To avoid this, lipids can be employed. Their instability and the consequent reduction of their average life hinder their clinical applications. Nevertheless, their core-shell structure presents countless advantages, especially for drug delivery. In the case of oily core nanocapsules, the pharmaceutical industry opts for lyophilization, especially if there are thermolabile compounds. Definitely, they result in promising structures as they offer a high capability of drug encapsulation, protection from degradation, and biocompatibility; they hardly irritate tissues and certain polymers have been observed to actively interact with biological fluids [4, 5].
