The LDHs biological hybrid promotes electron transfer via dual starvation enhancing tumor Ferroptosis/Apoptosis

Abstract

Current strategies for metabolic regulation within the tumor microenvironment (TME) often rely on exogenous drugs, leading to transient benefits and necessitating repeated administrations that frequently cause detrimental side effects. To address this, we have developed a novel bacterial biocatalytic reactor LDGM, which is fabricated by functionalizing Shewanella oneidensis MR-1 (MR-1) bacteria with DOX/GOx-loaded layered double hydroxide (LDH) nanosheets. This sophisticated biomaterial exhibits specific targeting towards hypoxic tumor areas, facilitating the controlled release of doxorubicin (DOX), glucose oxidase (GOx), and Fe³⁺. Crucially, MR-1 continuously metabolizes intratumoral lactate for its respiratory needs, thereby augmenting chemotherapy efficacy and combating tumor multidrug resistance. Moreover, under the hypoxic environment generated by GOx, MR-1 performs iron respiration, promoting the reduction of Fe³⁺ through electron transfer. This reactor is engineered to simultaneously induce ferroptosis and apoptosis by internally utilizing tumor lactate for respiration and engaging in iron respiration under hypoxic conditions. Our investigations in murine tumor models demonstrated that LDGM significantly suppresses tumor progression while simultaneously enhancing ferroptosis and apoptosis. Therefore, this living biomaterial presents a promising avenue for advancing cancer therapy by establishing continuous metabolic regulation of the intratumoral lactate/glucose microenvironment.