Inflammation-responsive biomimetic hybrid nanovesicles reverse stem cell senescence by up-regulating SIRT1 to treat periodontitis

Periodontitis is a chronic inflammatory condition affecting billions globally, posing a significant public health challenge due to its high prevalence and associated tooth loss. The inflammatory microenvironment engendered by periodontitis can induce cellular senescence and functional impairment in critical reparative cells, such as periodontal ligament stem cells (PDLSCs), severely compromising their osteogenic differentiation potential and thereby obstructing the regeneration and repair of periodontal tissues, particularly alveolar bone. Although existing fundamental treatments, including subgingival scaling, and surgical interventions can partially manage the disease, they exhibit notable limitations in eradicating deep-seated inflammation and effectively promoting structural bone regeneration. Consequently, there is an urgent need to develop novel biological treatment strategies aimed at reversing the senescent state of PDLSCs and enhancing their regenerative capacity. Flufenamic acid (FFA) is a widely utilized non-steroidal anti-inflammatory drug known for its notable anti-inflammatory and osteogenic properties. It holds significant potential for application in periodontal tissue engineering; however, its precise effects and underlying mechanisms remain inadequately understood. In this investigation, FFA effectively reversed the senescent state of periodontal ligament stem cells (PDLSCs), resulting in a marked down-regulation of pro-inflammatory, cellular senescence, and osteoclast differentiation-related markers, alongside an up-regulation of osteogenic differentiation-related markers. Furthermore, FFA significantly inhibited M1 polarization and osteoclast differentiation activity in macrophages and osteoclast precursor cells. Drug target screening and molecular docking analyses indicated that FFA mitigates PDLSC senescence and enhances their osteogenic capacity through activation of the SIRT1 signaling pathway. Additionally, this study employed the biological effects of M1 macrophage membranes to develop biomimetic hybrid nanovesicles (FFA@M1-LPs) designed to respond to inflammatory microenvironments. These findings suggest that FFA could be a promising new drug for periodontitis treatment and offer insights for developing drug delivery strategies to effectively regenerate periodontal tissue.