*2.9.2 Chitosan based nanoparticles*

Chitosan is a natural polysaccharide of glucosamine and N-acetyl glucosamine. Chitosan has some attractive features for being used in protein or peptide delivery [81]. Firstly, chitosan has high biocompatibility and low immunogenicity. Secondly, chitosan is a biodegradable polymer with high abundance. In the acidic environment, chitosan is protonated (**Figure 13**). This protonated form enhances the absorption of chitosan due to the interaction of the positively charged amino group with the cellular membrane [82–84]. This interaction leads to structural changes that opens the tight junction and allows the entry of proteins or peptides across the membrane. It is worth mentioning that chitosan exhibits absorption enhancing ability only in the acidic environment since it requires the protonated form of chitosan. Therefore, chitosan cannot act as an absorption enhancer in the neutral or basic environment [85, 86]. However, N-trimethyl chitosan (**Figure 13**) possess the absorption enhancing property over a wide range of pH, including the physiological pH. N-trimethyl chitosan-based nanoparticles loaded with insulin showed enhanced bioavailability of insulin [87]. N-trimethyl chitosan enhances the transport of proteins or peptides via both transcellular and paracellular pathways.

#### *2.9.3 Inorganic nanoparticles*

Inorganic nanoparticles are receiving more attention in the development of protein or peptide carriers due to some special properties. The protein or peptide of interest can be encapsulated inside the nanoparticle, which can provide protection against denaturation of the protein or peptide of interest. Thus, nanoparticles preserve both the structure and the biological function of the protein or peptide. Nanoparticles also prevent possible enzymatic hydrolysis and other degradation in the harsh environment of the GIT. Finally, nanoparticles improve the shelf life of the incorporated protein or peptide [88]. CaP nanoparticle has been used in

**Figure 13.** *Protonated (middle) and methylated (right) forms of chitosan (left).*

**Figure 14.** *Structure of a CaP-based insulin carrier.*

delivering protein (e.g., insulin) via the oral route. In this formulation, PEG-insulin and casein are encapsulated in the CaP nanoparticle (**Figure 14**). This formulation was shown to increase the half-life of insulin [89].
