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 (DCCMH) using metformin (Met) and α-cyano-4-hydroxycinnamic acid (CHCA) as ligands for coordination self-assembly with Cu ²⁺ , followed by loading of DOX and surface modification with HA. Upon internalization by cancer cells, DCCMH releases Cu ²⁺ , CHCA, Met, and DOX in response to high levels of GSH-H ₂ O ₂ within the tumor microenvironment (TME); Cu ²⁺ depletes GSH and generates Cu ⁺ that subsequently catalyzes H ₂ O ₂ to hydroxyl radical through a Fenton reaction; 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 abilities to synergistically combine chemo/chemodynamic therapy and remodel the TME, the DCCMH nMOFs inhibit murine hepatoma effectively. This study presents a feasible strategy for fabricating prodrug nano-MOFs which are capable of remodeling TME to improve efficacy through synergistic cancer therapy.