Bacterial Biohybrids With Dual Magnet and Hypoxia Tropism for Ferroptosis Activation in Deep Tumor Regions

ABSTRACT Effectively delivering therapeutics to deep tumor regions is crucial for successful treatment but remains a formidable challenge. The severe hypoxia common in these areas can inhibit various therapeutic‐induced cell death pathways, including ferroptosis. Herein, we present the design of a bacterial biohybrid (Ec@ZFOY) with dual magnetic and hypoxic tropism for targeted therapeutic delivery and ferroptosis activation in the deep tumor region. This biohybrid is constructed using hypoxia‐targeted Escherichia coli and magnetic Zn 0.16 Fe 1.24 O 4 (ZFO) nanoparticles loaded with YC‐1, a hypoxia‐inducible factor‐1α (HIF‐1α) inhibitor. ZFO exhibits peroxidase‐ and glutathione oxidase‐mimetic activities, catalyzing tumor‐derived H 2 O 2 into hydroxyl radical and inhibiting glutathione peroxidase 4, thereby inducing ferroptosis. Additionally, Ec@ZFOY demonstrates pH‐responsive YC‐1 release, which inhibits HIF‐1α and reduces lipid droplets, enhancing ferroptosis through the release of polyunsaturated fatty acids. Both in vitro and in vivo experiments confirm the significant therapeutic efficacy of Ec@ZFOY. This study unveils the design of magnetically and hypoxia‐tropic bacterial biohybrids for activating ferroptosis in deep tumor sites, highlighting their potential for other therapeutic delivery and disease modulation applications.