Novel biofilm-targeted therapeutics for oral infections: enzymes, EPS disruptors, phage/CRISPR, photodynamic and cold-plasma approaches - a systematic review.

Background: Microbial biofilms underpin the chronicity, recurrence and antimicrobial tolerance of most oral infections. As mechanical and antibiotic strategies are constrained by antimicrobial resistance and by the protective biofilm matrix, non-antibiotic, biofilm-targeted therapeutics have attracted intense interest. We systematically mapped and appraised five mechanistically distinct modalities - matrix-degrading (anti-biofilm) enzymes, extracellular polymeric substance (EPS) disruptors, bacteriophage and CRISPR-based therapy, antimicrobial photodynamic therapy (aPDT) and cold atmospheric plasma (CAP) - selected because each targets a different, non-antibiotic vulnerability of the biofilm. Methods: Following a PRISMA 2020 protocol (PROSPERO), PubMed, Embase, Web of Science and Scopus were searched from inception to January 2026. Results: Seventy-eight studies met the criteria; 58% (45/78) were Conclusion: On current evidence these modalities are best positioned as adjuncts that enhance, rather than replace, mechanical and antimicrobial therapy. Only aPDT currently has sufficient clinical evidence for consideration as an adjunct to conventional therapy; the remaining modalities remain investigational and require further translational and clinical development. Combination (matrix-first) strategies, targeted delivery, and standardised oral-biofilm models and clinical trials are priorities. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD420261428848.