Erythrocyte-Based Biomimetic MOFs as a Triple Epigenetic Regulator for Enhancing Anti-Leukemia Immunity

While therapeutic strategies targeting epigenetic dysregulation hold promise for leukemia, epigenetic drugs face several limitations, including low utilization rates, the emergence of resistance, and off-target effects. The hypoxic microenvironment in leukemia further impairs drug sensitivity. Here, we synthesized an MOF-based erythrocyte biomimetic nanoplatform to enhance immune responses against leukemia by targeting three epigenetic modifications. UiO-66-NH₂ was loaded with two epigenetic drugs, along with oxygen-rich erythrocytes (red blood cells, RBCs). MA272@MOF@RBC suppressed hypoxia-induced factor (HIF-1α) and its downstream oncogenes, thereby enhancing the efficacy of the epigenetic drugs. The drugs inhibited the growth of leukemia cells by targeting DNA and histone methylation while enhancing m⁶A-RNA methylation. MA272@MOF@RBC activated cytotoxic and memory T cells by increasing the antigenicity of leukemia cells. MA272@MOF@RBC also demonstrated immunotherapeutic effects on solid tumors. This was the first study to report the synthesis of triple epigenetic regulatory biomimetic MOFs with significant clinical potential for tumor immunotherapy.