Coordination Reprogramming of Fe‐Antibiotic Assemblies Enables Valence‐Gated β‐Lactam Reactivation

Reactivating legacy antibiotics offers a practical route to combat drug‐resistant infections, but requires delivery systems that coordinate bacterial engagement with pathogen‐triggered drug release. Here, we report DFC, a deferoxamine (DFO)‐reprogrammed Fe‐carbenicillin (Car) coordination nanoassembly that restores the activity of the legacy β‐lactam antibiotic Car against MRSA. DFC was fabricated via DFO‐mediated competitive coordination, transforming homogeneous Fe‐Car networks into heterogeneous Car‐Fe‐DFO structures. Computational modeling and spectroscopic analyses showed stronger Fe 3+ ‐DFO affinity than Fe 3+ ‐Car binding, DFO‐induced redistribution of the Fe‐centered ligand environment, and sharply weakened Fe‐ligand stability after Fe 3+ ‐to‐Fe 2+ conversion. This coordination reprogramming allowed DFC to remain assembled under nonreducing conditions but rapidly disassemble and release Car under reducing conditions or upon exposure to MRSA. DFC enhanced MRSA targeting, biofilm penetration, and intracellular Fe/Car‐associated accumulation, while Fe‐valence‐triggered destabilization promoted Car release, disrupted iron homeostasis, amplified oxidative stress and lipid peroxidation, and damaged the bacterial envelope. Collectively, these synergistic effects re‑established β‐lactam susceptibility, conferred robust antibacterial and anti‑biofilm efficacy, and markedly promoted pathogen clearance as well as tissue repair, as evidenced in both infected wound and osteomyelitis models. This study establishes competitive coordination reprogramming as a chemical strategy for coupling bacterial iron metabolism with antibiotic liberation and resistance reversal.