Multi-active phlorotannins boost antimicrobial peptide LL-37 to promote periodontal tissue regeneration in diabetic periodontitis

The bidirectional correlation between diabetes and periodontitis positions the latter as the most prevalent complication of the former. Rehabilitation of the periodontal tissues damaged by diabetic periodontitis presents a significant clinical challenge. The multifaceted nature of the pathogenesis of diabetic periodontitis necessitates a comprehensive approach in its treatment to mitigate its adverse effects. To address this, a temperature-sensitive hydrogel containing phlorotannins (PL) and antimicrobial peptide LL-37 was developed to shift the microenvironment of diabetic periodontitis from an exacerbated high-glycemic inflammatory state to a regenerative one. The addition of PL significantly enhanced the antimicrobial properties, stability, and safety of LL-37. Vitro experiments confirmed that PL/LL-37 had good biocompatibility and promoted osteogenic differentiation of bone. PL/LL-37 demonstrated antioxidant properties by scavenging DPPH free radicals and inhibiting NO production. Furthermore, PL/LL-37 effectively modulated macrophage polarization from a M1 phenotype to an M2 phenotype through NF-κB P-p65 inflammatory pathway, thereby reducing the release of pro-inflammatory cytokines and promoting the secretion of anti-inflammatory cytokines. Interestingly, it could downregulate the AGE-RAGE signaling pathway, exerting a protective effect against diabetes. In addition, PL/LL-37 could attenuate inflammation levels, inhibit osteoclast production, promote bone regeneration, inhibit apoptosis and decrease RAGE levels in a rat model of diabetic periodontitis. These combined features synergistically accelerate diabetic periodontal bone regeneration. Consequently, PL/LL-37 emerges as a promising candidate for clinical treatment of diabetic periodontitis. Scheme 1 PL/LL-37 promotes periodontal tissue regeneration in diabetic periodontitis. Firstly, PL/LL-37 disrupts the P. gingivalis bacterial biofilm and binds endotoxin to exert an antibacterial effect. Secondly, PL/LL-37 down-regulates the NF-κB P-p65 pathway, promoting macrophage M1 to M2 conversion for enhanced anti-inflammatory effects. Thirdly, PL/LL-37 scavenges DPPH free radicals and down-regulates iNOS and NO production, further enhancing its anti-inflammatory properties. Additionally, PL/LL-37 reduces osteoclast production while upregulating RUNX2, BSP, and OPG production for improved osteogenesis. Moreover, it decreases Bax production while increasing Bcl-2 expression to prevent apoptosis. Finally, by reducing RAGE accumulation and inhibiting the AGE-RAGE reaction process, PL/LL-37 exhibits a protective effect against diabetes. • PL has diverse biological activities, including antioxidant, anti-inflammatory, antimicrobial, and diabetic protection. • LL-37 has potent antimicrobial activity, providing robust evidence for its potential application in periodontitis treatment. • PL and LL-37 can form a temperature-responsive hydrogel, presenting an innovative approach for drug delivery and application. • PL was first introduced as a therapeutic approach for diabetic periodontitis, providing a novel perspective for future study.