A Self-Driven Bioreactor Based on Bacterium-Metal-Organic Framework Biohybrids for Boosting Chemotherapy <i>via</i> Cyclic Lactate Catabolism.

Abstract

The excessive lactate in the tumor microenvironment always leads to poor therapeutic outcomes of chemotherapy. In this study, a self-driven bioreactor (defined as SO@MDH, where SO is <i>Shewanella oneidensis</i> MR-1 and MDH is MIL-101 metal-organic framework nanoparticles/doxorubicin/hyaluronic acid) is rationally constructed <i>via</i> the integration of doxorubicin (DOX)-loaded metal-organic framework (MOF) MIL-101 nanoparticles with SO to sensitize chemotherapy. Owing to the intrinsic tumor tropism and electron-driven respiration of SO, the biohybrid SO@MDH could actively target and colonize hypoxic and eutrophic tumor regions and anaerobically metabolize lactate accompanied by the transfer of electrons to Fe³⁺, which is the key component of the MIL-101 nanoparticles. As a result, the intratumoral lactate would undergo continuous catabolism coupled with the reduction of Fe³⁺ to Fe²⁺ and the subsequent degradation of MIL-101 frameworks, leading to an expeditious drug release for effective chemotherapy. Meanwhile, the generated Fe²⁺ will be promptly oxidized by the abundant hydrogen peroxide in the tumor microenvironment to reproduce Fe³⁺, which is, in turn, beneficial to circularly catabolize lactate and boost chemotherapy. More importantly, the consumption of intratumoral lactic acid could significantly inhibit the expression of multidrug resistance-related ABCB1 protein (also named P-glycoprotein (P-gp)) for conquering drug-resistant tumors. SO@MDH demonstrated here holds high tumor specificity and promising chemotherapeutic efficacy for suppressing tumor growth and overcoming multidrug resistance, confirming its potential prospects in cancer therapy.