Abstract
Achieving periodontal regeneration in diabetic periodontitis (DPD) is hindered by a self-perpetuating vicious cycle of excessive oxidative stress and adaptive immune dysfunction. Here, using clinical samples, multi-omics profiling, and DPD rat model, we identified an association between oxidative stress and CD4+ T cell dysregulation. This process was characterized by reactive oxygen species (ROS) accumulation and Th17/Treg imbalance, which may contribute to progressive alveolar bone loss. To modulate this pathological process, we engineered a logic-gated hydrogel-nanoparticle hybrid system for hierarchical delivery of active vitamin D (AVD). This platform features a dynamic boronic ester crosslinked network that functions as a ROS-responsive switch. Upon exposure to the oxidative microenvironment, the matrix undergoes programmed degradation to scavenge ROS, triggering the rapid release of antibody-functionalized nanoparticles. These nanoparticles selectively target CD4+ T cells and deliver AVD intracellularly, where it modulates mitochondrial homeostasis and metabolic signaling pathways, thereby restoring T-cell immune homeostasis. Following this immune reset, the system transitions into a second phase where porous copper-based metal-organic frameworks provide sustained release of AVD and osteogenic Cu2+ to support long-term bone remodeling. By integrating redox-responsive actuation, targeted immunometabolic regulation, and sustained osteoimmunomodulation, this hierarchical system provides a promising therapeutic strategy for periodontal regeneration in diabetic periodontitis.