Engineered Bio‐Heterojunction Confers Extra‐ and Intracellular Bacterial Ferroptosis and Hunger‐Triggered Cell Protection for Diabetic Wound Repair

Nanomaterial‐mediated ferroptosis has garnered considerable interest in the antibacterial field, as it invokes the disequilibrium of ion homeostasis and boosts lipid peroxidation in extra‐ and intracellular bacteria. However, current ferroptosis‐associated antibacterial strategies indiscriminately pose damage to healthy cells, ultimately compromising their biocompatibility. To address this daunting issue, this work has designed a precise ferroptosis bio‐heterojunction (F‐bio‐HJ) consisting of Fe2O3, Ti3C2‐MXene, and glucose oxidase (GOx) to induce extra‐intracellular bacteria‐targeted ferroptosis for infected diabetic cutaneous regeneration. Fe2O3/Ti3C2‐MXene@GOx (FMG) catalytically generates a considerable amount of ROS which assaults the membrane of extracellular bacteria, facilitating the permeation of synchronously generated Fe2+/Fe3+ into bacteria under near‐infrared (NIR) irradiation, causing planktonic bacterial death via ferroptosis, Fe2+ overload, and lipid peroxidation. Additionally, FMG facilitates intracellular bacterial ferroptosis by transporting Fe2+ into intracellular bacteria via inward ferroportin (FPN). With GOx consuming glucose, FMG creates hunger protection which helps macrophages escape cell ferroptosis by activating the adenosine 5’‐monophosphate (AMP) activated protein kinase (AMPK) pathway. In vivo results authenticate that FMG boosts diabetic infectious cutaneous regeneration without triggering ferroptosis in normal cells. As envisaged, the proposed tactic provides a promising approach to combat intractable infections by precisely terminating extra‐intracellular infection via steerable ferroptosis, thereby markedly elevating the biocompatibility of therapeutic ferroptosis‐mediated strategies. A precise ferroptosis bio‐heterojunction (F‐bio‐HJ) consisting of Fe2O3, Ti3C2‐MXene, and glucose oxidase is developed to induce extra‐intracellular bacteria‐targeted ferroptosis for infected diabetic cutaneous regeneration. Under near‐infrared (NIR) irradiation, F‐bio‐HJ induces extracellular bacterial ferroptosis via photothermal, photodynamic, and chemodynamic properties and assists macrophages against intracellular bacteria via ferroportin‐mediated bacterial ferroptosis and hunger‐triggered AMPK pathway‐mediated cell protection, elevating the biocompatibility of ferroptosis‐mediated therapeutic strategies.