Reduction/pH-responsive disassemblable MOF-microbial nanohybrid for targeted tumor penetration and synergistic therapy

Nanomedicine that combines nanomaterials and nanotechnologies has been attracting intensive attention for tumor treatment and achieved significant advances. However, their therapeutic efficiency is still limited by the passive circulating and enrichment of the currently widely used nanomaterial carries. Instead, an active nanomaterial carrier with tumor-taxis-like behavior holds the potential to further leap tumor targeting and therapeutic efficiency. Herein, for the first time, we show that a tumor microenvironment responsive disassemblable approach, based on tumor-targeted Escherichia coli bacteria linked with degradable zeolitic imidazolate framework-8 (ZIF-8) through disulfide bond-contained polymers, can deliver multiple drugs into deep tumor tissue. The carried ZIF-8 nanoparticles will detach from the Escherichia coli via disulfide bond breakage under high concentration glutathione in tumor sites. Furthermore, the small size ZIF-8 nanoparticles can penetrate whole tumor tissue and release drug molecules (doxycycline and indocyanine green) upon pH-responsive degradation. Under light irradiation, indocyanine green generates reactive oxygen species and mild hyperthermia, realizing a photodynamic/photothermal/chemical synergistic therapy along with the doxycycline. In a mouse model, the as-prepared microbial nanohybrid accumulates and releases the therapeutics throughout the tumor tissue and shows a better tumor inhibition efficacy compared to the ZIF-8 and non-disassemblable ZIF-8/microbial platforms. Thus, this work may establish a new strategy for enhancing tumor penetration and targeting and improving treatment efficiency of nanomaterials through a tumor microenvironment responsive disassemblable microbial nanohybrid.