Remodeling tumor microenvironment using prodrug nMOFs for synergistic cancer therapy

Metal-organic frameworks (MOFs) hold tremendous potential in cancer therapy due to their remarkable structural and functional adaptability, enabling them to serve as nanocarriers for biopharmaceuticals and nanoreactors for organizing cascade bioreactions. Nevertheless, MOFs are predominantly utilized as biologically inactive carriers in most cases. Developing nanoscale prodrug MOFs suitable for biomedical applications remains a huge challenge. In this study, we have designed a novel prodrug nano-MOFs (nMOFs, named DCCMH) using metformin (Met) and α-cyano-4-hydroxycinnamic acid (CHCA) as ligands for coordination self-assembly with CuCl₂, followed by loading of doxorubicin (DOX) and surface modification with hyaluronic acid (HA). Upon internalization by cancer cells, DCCMH releases Cu^2+/+, CHCA, Met, and DOX in response to high levels of glutathione (GSH) and hydrogen peroxide (H₂O₂) within the tumor microenvironment (TME); Cu⁺ catalyzes the conversion of H₂O₂ to ·OH via the Fenton reaction while it was oxidized to Cu²⁺, which was subsequently further de-consumed of GSH; CHCA induces a further decrease in intracellular pH and promotes Fenton reactions by inhibiting lactate efflux; Met up-regulates tyrosine kinase activity and enhances the chemotherapy of DOX. With the ability to synergistically combine chemo/chemodynamic therapy (CT/CDT) and remodel the TME, the DCCMH NPs inhibit murine hepatoma effectively. This study presents a feasible strategy for fabricating prodrug nMOFs which are capable of remodeling TME to improve efficacy through synergistic cancer therapy.