Periodontal tissue regeneration in diabetic periodontitis (DPD) is hindered by a vicious cycle of excessive oxidative stress and adaptive immune dysfunction. In this study, using clinical samples, multi-omics analysis, and a DPD rat model, we found a link between oxidative stress and CD4+ T cell dysfunction. This process is marked by reactive oxygen species (ROS) accumulation and a Th17/Treg imbalance, which may lead to progressive alveolar bone loss. To modulate this pathological process, we designed a logic-gated hydrogel-nanoparticle hybrid system for stepwise delivery of active vitamin D (AVD). The platform has a dynamic boronate ester crosslinked network that acts as an ROS-responsive switch. When exposed to an oxidative microenvironment, the matrix undergoes programmed degradation to clear ROS, triggering rapid release of antibody-functionalized nanoparticles. These nanoparticles selectively target CD4+ T cells, delivering AVD into the cells, where it regulates mitochondrial homeostasis and metabolic signaling pathways, restoring immune balance in T cells. After the immune reset, the system enters the second phase, with a porous copper-based metal-organic framework continuously releasing AVD and osteogenic Cu2+. To support long-term bone remodeling, this layered system integrates redox-responsive control, targeted immunometabolic regulation, and sustained osteoimmune modulation, offering a promising therapeutic strategy for periodontal regeneration in diabetic periodontitis.
