Polyphenolic nanobattery charged adoptive macrophages for sepsis immunotherapy

Sepsis is a life-threatening systemic inflammatory syndrome triggered by infection that progresses to multi-organ dysfunction. Its pathogenesis is primarily driven by dysregulated macrophage polarization, which exacerbates hyperinflammation and tissue damage. Herein, we developed a charged macrophage (ChAR-M) powered by polyphenolic nanobatteries that enable the continuous delivery of antioxidant and anti-inflammatory signals. This design empowers ChAR-M to sustain M2 polarization, prevent reversion to the M1 phenotype under hostile microenvironments, and facilitate paracrine-mediated reprogramming of neighboring macrophages. In a murine sepsis model, ChAR-M outperformed control interventions by increasing CD206 + macrophages, suppressing CD80 + cells, attenuating inflammatory infiltration and oxidative stress, restoring immunometabolic balance, and inhibiting key pro-inflammatory signaling pathways—collectively promoting tissue repair and halting disease progression. Notably, ChAR-M also exhibited potent immunomodulatory effects on peripheral blood mononuclear cells obtained from clinical sepsis patients. This work represents a redefined approach to sepsis immunomodulation, offering a scalable therapeutic platform to reverse immunosuppression and improve clinical outcomes.