One-pot synthesis of Mn/Fe bimetal-doped metal-organic framework as multifunctional nanocarriers for esophageal cancer targeted therapy.

Chemodynamic therapy (CDT) offers new opportunities to eliminate cancer by killing tumor cells through the production of toxic hydroxyl radicals (·OH) in the tumor region. However, the efficiency of CDT is severely hampered by insufficient levels of hydrogen peroxide and large amounts of glutathione (GSH) in tumor cells. To address this issue, we developed Mn/Fe bimetallic metal-organic framework (MnFe-MOF) nanocarriers that could respond to acidic and GSH-rich conditions for loading ursolic acid (UA) and MTH1 siRNA (siMTH1), followed by surface modification with hyaluronic acid (HA). Finally, a nanoparticle named UA/siMTH1@MnFe-MOF@HA was developed for the treatment of esophageal cancer. Benefiting from HA-coated encapsulation, UA/siMTH1@MnFe-MOF@HA achieved Kyse-30 cell targeting and slow release of UA/siMTH1. The Mn/Fe ions doped in the nanoframework catalyzed the Fenton reaction in the tumor microenvironment with acidic pH and overexpression of GSH to promote reactive oxygen species (ROS) generation, and further amplified oxidative stress by consuming GSH, resulting in cell damage. Moreover, siMTH1 released by the nanoparticles can cause DNA damage and induce cellular senescence to kill cancer cells, while the released UA can induce G1 cell cycle arrest to inhibit cell proliferation, synergistically enhancing the therapeutic effect. UA/siMTH1@MnFe-MOF@HA exhibited outstanding tumor suppression in vitro and in vivo, with negligible systemic toxicity. This transition metal-doped multifunctional MOF enabled efficient CDT and provides a promising paradigm for esophageal cancer therapy.