Osteoimmune sequence reprogramming: staged triboelectric immunotherapy for chronic osteomyelitis via JAK2–STAT3 regulation

Abstract

Chronic osteomyelitis remains difficult to eradicate because persistent bacterial colonization is associated with disruption of the osteoimmune temporal sequence linking antibacterial immunity, inflammatory resolution, and bone regeneration. Here, a drug-free staged triboelectric immunotherapy is developed using a direct-current triboelectric nanogenerator (DC-TENG) to restore this disordered sequence instead of merely suppress inflammation or promote osteogenesis. Through systematic evaluation of DC-TENG electrical parameters, an optimized stimulation condition is identified that shows favorable cytocompatibility, enhances osteogenic differentiation, and directly suppresses Staphylococcus aureus growth and biofilm formation. RNA sequencing reveals osteoimmune dysregulation and attenuated JAK2–STAT3 signaling in chronic osteomyelitis bone marrow. Optimized triboelectric immunotherapy reactivates JAK2–STAT3 signaling in macrophages, promotes a pro-inflammatory and antibacterial phenotype, and increases antibacterial cytokine production, whereas STAT3 inhibition partially reverses these effects. In vivo , short-term triboelectric immunotherapy induces STAT3-dependent antibacterial immune activation, enhances T-cell responses, and reduces bacterial burden. This activation does not progress into persistent inflammation. Long-term profiling shows reduced cytokine and chemokine secretion, decreased JAK2–STAT3 activity, inflammatory resolution, collagen remodeling, and enhanced bone regeneration. These findings support a time-dependent osteoimmune response pattern following DC-TENG treatment, characterized by distinct short-term immune activation and long-term pro-resolving and regenerative responses, and support staged triboelectric immunotherapy as a drug-free preclinical strategy for chronic osteomyelitis treatment.