Targeting JAK2 with a multifunctional nanoinhibitor for long-lasting anti-inflammatory effects and bone repair.

Dysregulation of the JAK2/STAT3 pathway disrupts immune balance and tissue homeostasis, leading to persistent inflammation and subsequent bone loss. Yet, commonly used JAK2 inhibitors with hydrophobicity primarily suppress inflammation but often fail to provide sustained pharmacological effects and address ongoing inflammation-induced bone destruction. Here, using computer-aided drug design, we developed hydrophilic calcium-doped carbon dots (Ca-CDs) as a multifunctional nanoinhibitor targeting JAK2. The Ca-CDs can block the excessive activation of the JAK2/STAT3 pathway by binding to JAK2, thereby reducing the secretion of pro-inflammatory cytokines and exerting anti-inflammatory effects. Furthermore, the Ca-CDs promote bone regeneration under inflammatory conditions and serve as crosslinking junctions that facilitate the formation of a Ca-CDs-based alginate hydrogel, thereby enabling prolonged drug retention and controlled release. Their application in the representative inflammatory microenvironment of periodontitis successfully validated the efficacy of the Ca-CDs-based therapeutic strategy. Overall, targeting JAK2 with Ca-CDs nanoinhibitor offers a promising treatment option for JAK2-associated inflammatory diseases.