Formulation Redesigning of Itaconate Treats Periodontitis via Nrf2/TFAM‐Mediated Reprogramming of Mitochondrial Metabolism

ABSTRACT Periodontitis is the leading cause of tooth loss in adults. Unfortunately, inflammation remains poorly controlled and prone to relapse, even after removing the initial plaque biofilm. The unique metabolic properties of mitochondria in the periodontal microenvironment provide a promising target for novel therapeutic strategies against periodontitis. Here, we integrate metabolomics and network biology to elucidate the potential role of nuclear factor E2‐related factor 2/mitochondrial transcription factor (Nrf2/TFAM) in regulating mitochondrial metabolism in periodontitis. Based on this discovery, it is crucial to develop an innovative nanomedicine capable of effectively modulating the mitochondrial metabolism in periodontitis. Recently, itaconate (ITA), a key metabolite linking mitochondrial metabolism and inflammation, has emerged as a powerhouse in regulating immunity through Nrf2; however, its limited permeability hinders its application in biological systems. Therefore, we synthesize ITA‐based nano cocktail (INC) with cell permeability and improved biological functions. At the cellular level, INC activates Nrf2/TFAM to remodel mitochondrial metabolism and regulate macrophage immune homeostasis. In mouse models of periodontitis, INC successfully reprograms mitochondrial metabolism within the gingiva, leading to an improved inflammatory microenvironment. Our study elucidates the role of INC in modulating mitochondrial metabolism, thereby offering an innovative therapeutic strategy for the management of periodontitis and other clinical conditions resulting from mitochondrial abnormalities.