PLGA/HA sustained-release system loaded with liraglutide for the treatment of diabetic periodontitis through inhibition of necroptosis

Diabetes and periodontitis exhibit a bidirectional relationship, posing significant challenges for the treatment of periodontitis in patients with diabetes. Our previous studies showed that the hypoglycemic agent liraglutide (LIRA), together with glycemic control, had favorable therapeutic effects on diabetic periodontitis (DP), achieving a "two birds with one stone" effect. Therefore, exploration of the topical application of LIRA for treating DP is warranted. In this study, nanoparticles were loaded with LIRA using poly (lactic-co-glycolic acid) (PLGA), and their morphology, particle size, encapsulation efficiency, drug loading, and drug release profiles were characterized. These nanoparticles were further encapsulated with hyaluronic acid (HA) to form a LIRA@PLGA/HA sustained-release system. The cytotoxicity of LIRA@PLGA/HA was analyzed using CCK-8 assays, and its anti-inflammatory and osteogenic effects on periodontitis in diabetic rats were evaluated by histology, ELISA, and micro-CT analysis, while its influence on necroptosis-related factors was assessed using qRT-PCR and Western blotting. The results indicated that LIRA@PLGA (30000 Da) exhibited an encapsulation efficiency of 86.2 %, a drug loading capacity of 4.3 %, and a cumulative release of LIRA reaching approximately 60 % after 8 days, thereby meting the requirement for sustained release. Following 24 h of stimulation with various concentrations (0-20 mg/ml) of LIRA@PLGA/HA, the viability of human periodontal ligament cells (HPDLCs) remained above 85 %. Topical application for four weeks significantly inhibited the expression of the inflammatory factors TNF-α and IL-1β in gingival crevicular fluid and serum, reduced inflammatory cell infiltration in periodontal tissues, and attenuated alveolar bone resorption while improving alveolar bone microstructure, showing therapeutic effects similar to the commercial drug PERIOCLINE® (PERIO). Furthermore, LIRA@PLGA/HA reduced the expression of necroptosis-related factors RIPK1, RIPK3, and MLKL. In conclusion, these results suggest that topical application of LIRA@PLGA/HA is effective for the treatment of DP through inhibition of necroptosis, representing a promising treatment strategy.