Human dental caries is an intractable biofilm-associated disease caused by the symbiotic cariogenic bacteria, but how to target effectively eliminate cariogenic bacterial and their biofilms without affecting normal bacteria still remains great challenges. To address this issue, we reported Cu,Fe-doped chitosan-based nanozyme (i.e. CS@Cu,Fe) that exhibits well peroxidase-like activity at acidic environment of caries, and kill S. mutans and S. sanguinis without impacting the normal S. oralis. The synergistic interaction between Cu and Fe could effectively enhance the efficiency of electron transfer, promoting the production of hydroxyl radicals (·OH) and superoxide radical (·O2-) to selectively destroy the biofilm of S. mutans. Compared to curcumin and hexadecyl trimethyl ammonium bromide (CTAB) (control), the chitosan on the surface of CS@Cu,Fe not only showed the synergistic antibacterial activity, but also enabled the selectively eradication of S. mutans biofilm without affecting S. sanguinis and S. oralis biofilms. Furthermore, CS@Cu,Fe also exhibited excellent selective anti-symbiotic caries bacteria and targeted anti-biofilm properties to hybrid biofilm model of these co-existing bacteria under the same oral environment. Therefore, the CS@Cu,Fe nanozyme not only has potential for the treatment of dental biofilms, but also can offer new insights for the design of highly selective antibacterial and antibiofilm nanozyme.Copyright © 2024 Elsevier B.V. All rights reserved.