A Bone Marrow-Targeted Nanomodulator as a Histone Lactylation Inhibitor for Reversing Immune Tolerance in Multiple Myeloma

The metabolic–epigenetic symbiosis between tumor cells and macrophages in the bone marrow microenvironment (BMM) plays a crucial role in immune evasion and therapeutic resistance in multiple myeloma. Here, we present a copper-based nanomodulator, NanoCURE (Cu-activated Reprogramming Eraser), that targets the glycolysis-lactate-lactylation axis to reprogram metabolism and epigenetics in the BMM. To construct NanoCURE, lactate oxidase (LOx) and bortezomib (BTZ) are coencapsulated within a tumor-activated Cu2+ nanoassembly, facilitating bone marrow (BM)-specific delivery via an in vivo hijacking monocyte/macrophage pathway. Mechanistically, NanoCURE acts as a multifunctional modulator that disrupts the metabolic–epigenetic positive feedback loop by directly blocking histone lactylation through site-specific binding while simultaneously suppressing the upstream Akt/mTOR/c-Myc signaling axis. Moreover, NanoCURE can trigger the overproduction of reactive oxygen species (ROS), leading to mitochondrial dysfunction that amplify epigenetic interference. Consequently, these synergistic effects effectively disrupt the metabolic and epigenetic support of MM and reverse immunosuppressive M2 macrophage polarization to enhance the therapeutic effect of proteasome inhibitors in an orthotopic xenograft mouse model. Furthermore, NanoCURE achieves precise bone marrow enrichment via monocyte hijacking while maintaining low systemic copper levels, thereby ensuring high biosafety, preserving hematopoietic integrity, and exhibiting no observable organ toxicity. In summary, this work introduces a carrier-as-drug platform that targets the glycolysis-lactate-lactylation axis to enable in situ metabolic–epigenetic-immune reprogramming, offering a promising strategy to overcome therapeutic resistance in multiple myeloma.