The oral cavity is a complex microenvironment that is vulnerable to various physical, chemical, and microbial injuries, resulting in oral diseases. These include soft tissue diseases, such as gingivitis, aphthous ulcers, and other mucosal diseases; hard tissue diseases, such as caries, fractures, and bone defects; and combined soft and hard tissue diseases, such as periodontitis and tumors. Therefore, in stomatology, it is necessary to find a medical material that features different characteristics under different treatment conditions. In recent years, many researchers have found that nano-chitosan offers application advantages against various oral diseases ^{[1][2][3][4][5][6]}[1,2,3,4,5,6].

Chitosan (CS) is a cationic polymer composed of β-(1-4)-linked d-glucosamine and N-acetyl-d-glucosamine ^[7][8][7,8]. The cationic properties of CS enable it to combine with polyanions to form complexes; it also features gelation characteristics [9]. Furthermore, many of the characteristics of CS, such as its low water and acid solubility, good biodegradability, good biocompatibility, non-toxicity, antibacterial ability, anti-plaque effects, and anti-adhesion properties, allow the application of CS in many fields, especially in stomatology ^[7][9][10][7,9,10]. Intermolecular hydrogen bonding enables nano-CS to form stable nanogels, which feature a smaller size and higher specific surface area than CS ^{[10][11][12][13]}[10,11,12,13]. Moreover, nanoscale confers certain characteristics upon nano-CS that are not present in CS. These characteristics include higher permeability, better biocompatibility, higher charge density, and greater support for the development of cells. These unique characteristics of nano-CS enable its abundant applications in stomatology (shown in Figure 1).

In different treatment methods for oral diseases (such as mucosal diseases, periodontitis, etc.), local drug administration with targeted- and sustained-release characteristics is preferable to systemic administration. Local administration can reduce the toxicity and side effects of drugs that are absorbed by other tissues or organs ^[4][14][4,14]. However, determining how locally administered drugs can be retained in the targeted tissue for a long time and released slowly in the presence of saliva and food-chewing remains challenging [4].

Chitosan is often used as a carrier for targeted drug delivery, to sustain drug effects at a subcellular scale, to achieve cellular targets with high accuracy, to achieve maximum therapeutic effect, and to decrease adverse effects ^[15][16][17][15,16,17]. In this approach, active drug substances are dissolved, entrapped, or encapsulated and absorbed or attached to the drug carriers ^[16][18][16,18]. Cationic CS can be electrostatically adsorbed with mucin carboxyl groups on the mucosal and enamel surface, in order to stay in the oral cavity for more than 6 h, and the film-forming ability of CS makes the drugs or biomolecules it is carrying release slowly ^{[3][4][18][19]}[3,4,18,19]. When the pH of the oral environment is lower than 6.5 (the ionization constant of CS), CS can dissolve in water and release any drug or bioactive molecule it is carrying [20]. For instance, nano-CS has the ability to stably and continuously increase the release of NaF in an acidic environment with a pH of 5 to 7 ^[1][20][1,20]. Therefore, as a drug carrier, CS has considerable application prospects in acidic oral microenvironments. The small size of nanoscale increases the probability of biological membrane penetration by drugs carried by nano drug carriers, significantly increasing the bioavailability of the drugs and reducing their toxicity and side effects ^[17][21][17,21]. For example, compared to silver diamine fluoride alone, nano silver fluoride (NSF), which is composed of nanoparticles of silver and CS, has a lower effective dose against Streptococcus mutans and lower toxicity [22].

Nano-CS may have many effects in local oral administration, such as targeted adhesion to the surface of oral tissues, slow drug release, resistance to acidic oral environments, the improvement of drug bioavailability, and so on.

Nano-CS obtained by gamma irradiation, which is covered by bacterial cellulose, could significantly inhibit microbial strains in difficult-to-heal oral wounds [23]. This antimicrobial activity can inhibit bacterial invasion to protect the wound from secondary infection [23]. Nano-CS has a disc-like shape and an average diameter in the range of 40 to 60 nm. However, the release of nano-CS from BC is slow and continuous [23]. Tee [11] formed nano-CS loaded with recombinant human keratinocyte growth factor (nano-CS/rHuKGF) to increase the stability of rHuKGF and prevent rHuKGF proteolysis in saliva. Hydroxy-modified glucose CS (HGC) nanoparticles were synthesized by conjugating hydrophilic glycol CS with hydrophobic β-cholanic acid, and the synthesized nanoparticles showed good solubility in neutral solution, could self-assemble in neutral solution, and could encapsulate drugs for sustained release ^[24][25][24,25]. The core of the HGC nanoparticles was composed of hydrophobic β-cholanic acid covered by a hydrophilic cationic CS shell (shown in Figure 2). Drugs such as anionic trichloroacetic acid (TCA) and epidermal growth factor (EGF) can be loaded through ionic bonds (shown in Figure 3) ^[17][26][17,26]. The nano-controlled release system significantly reduced the danger of applying TCA locally [17]. Further, the nano-controlled release system upregulated the cell survival genes of the PI3K-AKT signaling pathway [26]. The system significantly increased the expression of gingival growth factors and soft tissue growth-related genes and significantly promoted soft tissue regeneration in animal experiments [17]. Therefore, HGC nanoparticles are an ideal nano-controlled release system for improving soft tissue regeneration. Doxycycline covered by nano-CS was utilized as an adjunct to basic periodontal therapy for moderate chronic periodontitis. Compared to traditional doxycycline and placebo-CS, gingival crevicular fluid levels of interleukin (IL)-6 and tumor necrosing factor-α significantly decreased, which was thought to have resulted from reduced inflammatory processes associated with tissue destruction in periodontal pockets. As a local delivery system, doxycycline covered by nano-CS is easy to apply and insert, which is suitable for the dimensions of the pocket, and it is easy to access the bottom of the pocket, reducing the pain of ingesting the medicine [27].