Stimuli-responsive, antimicrobial-loaded nanocarriers for oral biofilm control and microbiome restoration

Nanotechnology has provided thousands of novel nano-antimicrobials possessing features uncommon in clinically available antimicrobials. Here, nanocarriers loaded with conventional antimicrobials and responding to environmental changes upon entry into oral biofilms are reviewed. Supra-gingival biofilms are characterized by acidic pH, the presence of bacterial enzymes, and the development of hypoxia in deeper layers. Sub-gingival biofilms are slightly alkaline, with hypoxia occurring over their entire depth. Upon entering biofilms, negatively charged, pH- and/or hypoxia-responsive nanocarriers become positively charged. This charge reversal leads to electrostatic double-layer attraction between positively charged nanocarriers towards negatively charged, water-filled channel walls in biofilms, enhancing their accumulation in a biofilm. Degradation of bacterial enzyme-responsive nanocarriers causes in-biofilm release of antimicrobial cargo, yielding higher local antimicrobial concentrations than can be achieved through their direct, oral administration without harming soft tissues. Enhanced antibiofilm activity after in-biofilm antimicrobial release from biofilm-responsive micelles and liposomes has been demonstrated in vitro towards single-species Streptococcus mutans and Staphylococcus aureus biofilms or in vivo using specific-pathogen-free rodents inoculated with selected pathogens. This preferential antibacterial activity regulated the microbial composition of ex vivo human oral biofilm towards a more healthy microbiome composition. Although clinical confirmation is limited, the potential benefits of stimuli-responsive, antimicrobial-loaded nanocarriers for oral biofilm control and microbiome restoration are worth further investigation towards clinical translation.