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

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_0.16Fe_1.24O₄ (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 H₂O₂ 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.