Han Qi, Li Jiaqi, Deng Hao, Shi Sirong, Zhou Mi, Cai Xiaoxiao, Chen Yu, Lin Yunfeng
State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, Department of Oral Pathology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China.
State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, 610041, China.
Small. 2025 May;21(20):e2411740. doi: 10.1002/smll.202411740. Epub 2025 Jan 19.
Diabetic periodontitis presents a unique therapeutic challenge, primarily due to its chronic inflammatory profile and the associated bone loss driven by immune dysregulation. Metformin (Met) is recognized for its potent anti-inflammatory properties, yet its limited cellular uptake has hindered its clinical effectiveness in diabetic periodontitis. A tetrahedral framework nucleic acid (tFNA)-based delivery system is developed to enhance Met cellular uptake and investigate its effects on diabetic periodontitis in this study. The tFNA-loaded Met complex (TMC) demonstrates efficient Met loading efficiency and rapid cellular internalization. These results show that in vitro, TMC significantly inhibited pro-inflammatory cytokines and matrix metalloproteinaseat both mRNA and protein levels under high glucose conditions. Mechanistically, TMC suppresses NLRP3-mediated pyroptosis by downregulating NLRP3, Caspase-1, Caspase-11, and GSDMD, ultimately reducing Mature-IL-1β and Mature-IL-18 production. Furthermore, TMC activates AMPK while inhibiting NF-κB signaling, thus mitigating the inflammatory response in diabetic periodontitis. In vivo, intraperitoneal administration of TMC in a diabetic periodontitis mouse model significantly reduces inflammatory cell infiltration, collagen degradation, and osteoclast formation, thus alleviating alveolar bone loss. These findings highlight the therapeutic potential of tFNA as an efficient Met delivery vehicle to tackle diabetic periodontitis-associated inflammation and bone resorption, providing a promising strategy for managing diabetic complications.
糖尿病性牙周炎带来了独特的治疗挑战，主要是由于其慢性炎症特征以及免疫失调导致的相关骨质流失。二甲双胍（Met）因其强大的抗炎特性而闻名，但其有限的细胞摄取阻碍了其在糖尿病性牙周炎中的临床疗效。在本研究中，开发了一种基于四面体框架核酸（tFNA）的递送系统，以增强Met的细胞摄取并研究其对糖尿病性牙周炎的影响。负载tFNA的Met复合物（TMC）显示出高效的Met负载效率和快速的细胞内化。这些结果表明，在体外，TMC在高糖条件下在mRNA和蛋白质水平上均显著抑制促炎细胞因子和基质金属蛋白酶。从机制上讲，TMC通过下调NLRP3、半胱天冬酶-1、半胱天冬酶-11和GSDMD来抑制NLRP3介导的细胞焦亡，最终减少成熟白细胞介素-1β和成熟白细胞介素-18的产生。此外，TMC激活AMPK同时抑制NF-κB信号传导，从而减轻糖尿病性牙周炎中的炎症反应。在体内，在糖尿病性牙周炎小鼠模型中腹腔注射TMC可显著减少炎症细胞浸润、胶原降解和破骨细胞形成，从而减轻牙槽骨丧失。这些发现突出了tFNA作为一种有效的Met递送载体在应对糖尿病性牙周炎相关炎症和骨吸收方面的治疗潜力，为管理糖尿病并发症提供了一种有前景的策略。
