Therapeutic Vaccines Based on Iron-Coordinated Metal-Phenolic Networks for Eradicating Drug-Resistant Staphylococcus aureus

Drug-resistant Staphylococcus aureus (DRSA) infections present a formidable therapeutic challenge severely threatening human health. To address this, we engineered a metal−phenolic network (MPN) platform that co-immobilizes whole-cell DRSA with immunostimulatory metal ions (i.e., Fe3+, Mn2+, Zn2+) under mild conditions. Among these, the iron-coordinated MPN (SA@FeMPN) exhibited superior potency, leveraging a dynamic valence transition mechanism to robustly amplify the TLR2/NF-κB signaling. This mechanism promoted functional polarization of macrophages to the M1 state and drove dendritic cell maturation. In a murine systemic infection model, SA@FeMPN elicited robust cellular and humoral immunity, achieving a 2−18-fold greater reduction in bacterial burden across major organs compared to other MPNs, and established durable immunological memory to prevent infection relapse. Collectively, this work establishes iron-coordinated MPNs as a rational design platform for next-generation immunotherapy and identifies SA@FeMPN as a promising therapeutic vaccine candidate that not only eradicates established DRSA infections but also confers lasting protection against recurrence.