Biomimetic Jmjd3-Protac Nanotherapeutics For Diabetic Periodontitis Therapy

Diabetic periodontitis (DP) is characterized by impaired periodontal tissue repair due to chronic inflammation, with current therapeutic strategies predominantly relying on systemic glycemic control, which fails to achieve localized precision modulation. JMJD3, a histone demethylase, plays a pivotal role in macrophage polarization, regulating gene expression not only through its enzymatic activity but also via an independent of its demethylase activity in immune responses. While existing JMJD3 inhibitors exclusively target its histone demethylase function.This study aims to develop a novel therapeutic strategy to disrupt the inflammatory cascade by targeting the independent of its demethylase activity of JMJD3. To achieve site-specific delivery, we engineered a pH/ROS responsive nanoparticle (PLGA-JMJD3-PROTAC) camouflaged with macrophage membranes (MM), P-PLGA-MM@NPs. In vitro studies confirmed that JMJD3 activates inflammatory gene transcription in an H3K27me3-independent manner, thereby reprogramming macrophage phenotypes. In vivo studies,treatment with P-PLGA-MM@NPs significantly reduced JMJD3 expression and pro-inflammatory cytokine levels in diabetic periodontal tissues, while promoting periodontal tissue repair and regeneration. Our bio-mimetic nano-delivery system demonstrated efficient targeting to inflammatory periodontal tissues and successful degradation a novel nonclassical function of JMJD3. The pH/ROS dual-responsive release mechanism ensured controlled drug delivery in the pathological microenvironment, optimizing therapeutic efficacy while minimizing off-target effects. This study establishes a strategy that integrates epigenetic regulation, microenvironment reprogramming, and tissue regeneration for DP treatment.