**Background:** Dental caries is the most common oral disease, affecting nearly 3.5 billion people globally, with prevalence rates reaching 100% among 12-year-old adolescents in low-income countries and 80% in lower-middle-income countries. Untreated dental caries in permanent teeth is the most common health condition according to the WHO. Caries is a multifactorial chronic infection caused by bacterial fermentation of carbohydrates, leading to enamel demineralization and cavity formation. The complex architecture of oral biofilms—organized aggregates of microorganisms (only 5–25% bacterial cells, remainder glycocalyx) joined by an extracellular polymeric matrix—makes treatment challenging. The oral cavity hosts over 700 bacterial species, with Streptococcus mutans playing a key role in biofilm organization through production of exoenzymes like glucosyltransferase that synthesize exopolysaccharides from sucrose and starch. This review summarizes and discusses liquid crystal systems and various nanotechnology-based drug delivery systems used to prevent and treat dental caries.
**Methods:** This is a narrative review that synthesizes findings from published studies on drug delivery systems for dental caries. The authors searched for studies involving liquid crystalline systems, liposomes, nanoemulsions, polymeric nanoparticles, hydrogels, dendrimers, polymeric micelles, and inorganic nanoparticles (silver, zinc, calcium, and titanium). They also summarized clinical trials registered on ClinicalTrials.gov that adopted nanoparticles for dental caries. The review covers studies using in vitro models, in vivo animal models, and available clinical data.
**Key Results:** The review presents extensive data on multiple drug delivery systems. For liquid crystalline systems (LCS): Aida and coworkers developed an LCS delivering β-defensin-3 peptide that showed time-dependent antimicrobial effect against S. mutans with reduced cytotoxicity compared to free peptide. Calixto and coworkers developed LCS containing p1025 peptide that showed equivalent biofilm eradication compared to chlorhexidine with HaCaT cell viability up to 70%. Bernegossi and coworkers developed KSL-W-loaded LCS that completely eradicated colony-forming units in multispecies biofilm models. For liposomes: Yamakami and coworkers showed nisin-loaded cationic liposomes had 2-fold higher antimicrobial activity than control, with 41% release after 2 h versus 80% for control. Zhou and coworkers developed pH-responsive doxycycline-loaded liposomes with t1/2 = 0.75 h at pH 4.5 versus 2.3 h at pH 6.8. For nanoemulsions: Ramalingam and coworkers developed cetylpyridinium chloride nanoemulsion that inhibited microorganisms 9- to 27-fold greater than chlorhexidine. Li and coworkers developed chlorhexidine acetate-loaded nanoemulsion (63.13 nm) that promoted 95.07% bacterial death within 5 min versus 73.33% for chlorhexidine. For polymeric nanoparticles: Aliasghari and coworkers showed chitosan nanoparticles decreased biofilm formation of S. mutans by 88.4%, S. salivarius by 93.4%, S. sobrinus by 78.9%, and S. sanguis by 72.6%. For hydrogels: Ren and coworkers developed chitosan hydrogel with QP5 peptide showing almost 100% inhibition of biofilm formation and 50% surface micro-hardness recovery. For dendrimers: Zhou and coworkers developed triclosan-loaded PAMAM dendrimers that promoted almost full remineralization of dentine after 4 weeks with sustained release for up to 48 h. For polymeric micelles: Xu and coworkers developed tannic acid and NaF-loaded micelles (300 nm) that showed superior remineralization effect compared to free drugs and significantly higher anti-cariogenic effect than conventional chlorhexidine treatment in vivo. For inorganic nanoparticles: Xiaoxue Yin and coworkers reported that 89% of studies involving silver nanoparticles investigated their antibacterial properties. Mirhosseini and coworkers found greatest inhibition of S. mutans with ZnO nanoparticles of 20–40 nm. Elgamily and coworkers showed nanocomplexes of calcium phosphate nanoparticles with probiotics had higher mean zone of inhibition than calcium phosphate alone. Araújo and coworkers demonstrated that 5% TiO2 nanotubes incorporated into glass ionomer cement presented higher antibacterial properties against S. mutans compared to 3% and 7% concentrations.
**Clinical Implications:** The review identifies that mucoadhesive systems, particularly liquid crystalline systems with in situ gelling properties, represent a promising strategy for increasing drug residence time in the oral cavity. The combination of drug delivery systems with remineralization agents (e.g., fluoride-loaded calcium phosphate nanoparticles, dendrimers, liposomes) offers potential for simultaneous anti-biofilm and reparative therapy. However, the authors emphasize that the majority of research uses in vitro models, with few clinical trials available—primarily involving silver nanoparticles (e.g., NCT05231330, NCT01950546, NCT03186261, NCT04929509), zinc oxide nanoparticles (NCT03478150), copper and zinc nanoparticles (NCT03635138), and polymeric/titanium dioxide nanoparticles (NCT04365270). The authors conclude that more clinical studies are needed to understand the effect of each system on preventing and treating oral caries, particularly for lipid- and polymer-based systems.