Iron‐Metabolism–Modulating Carbon Dots Controllably Orchestrates Antibacterial and Immunoregulatory Synergy for Effective Bacterial Sepsis Therapy

ABSTRACT Bacterial sepsis is a life‐threatening condition marked by uncontrolled infection and immune dysregulation, in which iron metabolism critically influences pathogen proliferation and host inflammatory. Herein, we designed and synthesized functional diethylenetriaminepentaacetic acid–spermidine carbon dots (D‐CDs), which exerted dual antibacterial and immunomodulatory effects by targeting iron metabolism. D‐CDs exhibited high affinity for Fe 3+ , effectively chelating Fe 3+ to induce “iron starvation” in bacteria, leading to metabolic disruption and increased oxidative stress, as evidenced by altered expression of gene associated with iron acquisition, energy metabolism, and oxidative stress defense. Furthermore, D‐CDs displayed potent antibacterial activity against bacteria containing clinical isolated resistant strains. Concurrently, D‐CDs protected host macrophages by attenuating ferroptosis through activation of the Nrf2/HMOX1 pathway and inhibition of the NF‐κB pathway, thereby restoring redox balance and promoting polarization toward the anti‐inflammatory M2 phenotype. In the two rat models of sepsis, induced by intravenous administration of bacterial suspension and by cecal ligation and puncture, D‐CDs significantly improved survival rates, reduced systemic bacterial burden, and alleviated multi‐organ inflammatory injury. Taken together, these findings suggest that iron metabolism centered modulation as a dual‐targeting strategy possess brilliant future for treating severe bacterial infections through integrating antibacterial action with immune homeostasis.