Table 5.

Preparation methods of chitosan NPs.

Preparation Methods	Mechanism	Advantages	Disadvantages
Ion crosslinking [142]	Interaction between crosslinking agent and the amino or carboxyl groups of chitosan NPs.	The preparation process itself has no organic solvent; the reaction conditions are simple, mild, and controllable.	Not completely immune to gastric acid degradation; low solubility.
Polyelectrolyte complexation [143,144]	Interactions between oppositely charged polyelectrolytes.	Two- or three-step process; the equipment requirements are not demanding, and the conditions are mild.	Stability is susceptible to pH.
Desolvation [145]	Insolubility of chitosan in alkaline media.	High nanoparticle formation rate; improved physical stability.	Inhomogeneous distribution of NPs; difficulty in synthesizing smaller-sized chitosan NPs.
Emulsification [146,147,148,149,150]	The oil and water phases are emulsified; then, the solvent is removed.	Two- to three-step process; no need for sonication or homogenizers.	Causes significant toxicity to tissues or cells; poor stability.
Spray drying [151,152]	Amino groups can be protonated by acids.	Re-dispersibility; enables easier synthesis of smaller sizes compared other methods; low toxicity.	The particle size is not easy to control; the particles are irregularly shaped and sticky.
Covalent crosslinking [153,154]	Formation of covalent bonds between chitosan NPs and crosslinking agents.	Controllable drug release.	Cytotoxic.
Reverse micelle [153,155]	Trans-interaction between chitosan NPs and crosslinking agent.	One-step process; good dispersion.	Causes significant toxicity in tissues or cells.