Breaking Iron Homeostasis: Iron Capturing Nanocomposites for Combating Bacterial Biofilm

Abstract Given the scarcity of novel antibiotics, the eradication of bacterial biofilm infections poses formidable challenges. Upon bacterial infection, the host restricts Fe ions, which are crucial for bacterial growth and maintenance. Having coevolved with the host, bacteria developed adaptive pathways like the hemin‐uptake system to avoid iron deficiency. Inspired by this, we propose a novel strategy, termed iron nutritional immunity therapy (INIT), utilizing Ga‐CT@P nanocomposites constructed with gallium, copper‐doped tetrakis (4‐carboxyphenyl) porphyrin (TCPP) metal–organic framework, and polyamine‐amine polymer dots, to target bacterial iron intakes and starve them. Owing to the similarity between iron/hemin and gallium/TCPP, gallium‐incorporated porphyrin potentially deceives bacteria into uptaking gallium ions and concurrently extracts iron ions from the surrounding bacteria milieu through the porphyrin ring. This strategy orchestrates a “give and take” approach for Ga 3+ /Fe 3+ exchange. Simultaneously, polymer dots can impede bacterial iron metabolism and serve as real‐time fluorescent iron‐sensing probes to continuously monitor dynamic iron restriction status. INIT based on Ga‐CT@P nanocomposites induced long‐term iron starvation, which affected iron‐sulfur cluster biogenesis and carbohydrate metabolism, ultimately facilitating biofilm eradication and tissue regeneration. Therefore, this study presents an innovative antibacterial strategy from a nutritional perspective that sheds light on refractory bacterial infection treatment and its future clinical application.