Microenvironment-responsive multi-enzyme cascade nanosystem for the treatment of early caries

The mechanism underlying antibacterial and in situ mineralization. • The nanosystem can responsively degrade templates and release functional components in cariogenic microenvironment. • The nanosystem achieved antibacterial and mineralization effects via a multi-enzyme cascade reaction. • The bifunctional multi-enzyme cascade nanosystem showed good biosafety. Oral diseases associated with dental biofilms have become one of the frontiers in clinical research due to their complexity. Dental caries is a typical biofilm driven disease resulting from the diet and microbiota-matrix interactions, and it remains a substantial clinical challenge to halt the progression of caries and simultaneously repair the damaged enamel. In this regard, an oral microenvironment-responsive strategy was put forward to develop a multi-enzyme cascade nanosystem possessing antibacterial and in situ mineralization properties. During application in the oral cavity, starch was hydrolyzed by α-amylase, thereby releasing calcium phosphate prenucleation clusters (CaP-PNCs) for in situ remineralization of demineralized enamel, and providing the hydrolysis product glucose. Subsequently, glucose oxidase (GOD) conjugated to dextran-coated iron oxide nanozyme (Dex-IONP-GOD, DIG) catalyzed the production of H 2 O 2 from glucose. Under the acidic caries microenvironment, IONP with POD-like activity can trigger H 2 O 2 to generate reactive oxygen species. This process exhibited bactericidal activities and effectively inhibited the adhesion and biofilm formation of Streptococcus mutans . This bifunctional multi-enzyme cascade nanosystem accomplishes the adaptive initiation of pathogen elimination and in situ mineralization by its environmental responsiveness, rather than relying on the exogenous substrates, which thus provides a potential strategy for preventing and treating dental caries.