LL-37-based oral antimicrobial therapeutics: translational challenges and future directions-a narrative review

LL-37 is an antimicrobial peptide involved in antimicrobial defence, inflammatory regulation, tissue repair, and bone regeneration in the oral cavity. Salivary and gingival crevicular fluid LL-37 levels are associated with disease activity and treatment responses. Although there is solid mechanistic and preclinical data on LL-37, research on clinical applications of this remarkable peptide seem to be stalled due to a multitude of factors. The use of LL-37 in clinical practice is affected by proteolytic degradation, cytotoxicity at higher concentrations, microbial tolerance, biofilm protection, rapid salivary clearance, and high production costs. Our review provides a comprehensive update emphasizing the key gaps in LL-37 research and the translational challenges faced by researchers. We also suggest a three-pronged roadmap to future approaches comprising (i) rational peptide engineering and smart nanocarrier-based delivery, (ii) host-directed induction of endogenous LL-37 via vitamin D and short-chain fatty acid pathways, and (iii) standardisation of salivary/gingival crevicular fluid LL-37 as a non-invasive biomarker, aimed at developing LL-37 as a viable diagnostic and therapeutic agent in periodontal disease, dental caries, endodontic infections, oral mucosal disorders, and oral squamous cell carcinoma. Peptide derivatives, nanocarrier-based delivery systems, combination therapy, and vitamin D-mediated induction are being studied to improve its stability and therapeutic activity. LL-37 may have strong applications in oral diagnosis, prevention, and treatment of oral diseases, if the safety, efficacy, and delivery methods are effectively enhanced.