Stability and biocompatibility of hBD3 with different chiral configurations and their therapeutic efficacy in periodontitis

Periodontitis is characterized by progressive destruction of the periodontal attachment apparatus caused by dental plaque accumulation, which can lead to tooth loosening and permanent loss. Human β-defensin 3 (hBD3) exhibits broad-spectrum antibacterial activity and exerts critical immunomodulatory functions. Modifying amino acid chirality represents a novel strategy for the development of next-generation antibacterial agents. In this study, D-hBD3 and L-hBD3 were synthesized via solid-phase peptide synthesis, with recombinant hBD3 (r-hBD3) as control, and their therapeutic efficacy was evaluated in experimental periodontitis mice. Our findings demonstrated that D-hBD3 exhibited remarkable stability, potent antibacterial activity <i>in vitro</i>, and <i>in vivo</i> therapeutic efficacy comparable to conventional antibiotics, r-hBD3 and L-hBD3. Mechanistically, D-hBD3 regulated immunity by downregulating pro-inflammatory TNF-α, upregulating anti-inflammatory IL-10, promoting intestinal macrophage polarization to M2 phenotype, and selectively inhibiting oral pathogens while preserving intestinal microbiota homeostasis. Collectively, this study provides critical evidence supporting D-hBD3 as a cost-effective therapeutic candidate for periodontitis.