CXCR4-targeted lipid nanozymes for metastasis blockade and immune microenvironment reprogramming in hematological...

Hematological malignancies are characterized by pronounced metastatic potential associated with the chemokine receptor 4/stromal cell-derived factor-1α (CXCR4/CXCL12) signaling axis, high relapse rates, and a profoundly immunosuppressive tumor microenvironment, all of which severely limit the long-term efficacy of existing therapeutic strategies. Herein, we developed a CXCR4-targeted lipid nanozyme platform (Pt-LNP@E5), in which platinum nanozyme catalytic units and E5 peptide were hierarchically integrated to synergistically achieve metastasis blockade and immune microenvironment remodeling. E5 peptide-mediated CXCR4-specific recognition enabled precise tumor cell accumulation of Pt-LNP@E5 and effectively antagonized CXCR4/CXCL12-driven metastatic signaling, thereby markedly suppressing tumor cell migration and dissemination. Meanwhile, the lipid nanocarrier significantly increased the systemic circulation half-life of the platinum nanozyme and maintained catalytic activity. Within the tumor cell microenvironment, the catalytic system selectively generated reactive oxygen species, which not only induced efficient tumor cell killing but also promoted the transition of the immune microenvironment from an immunosuppressive to an activated state, thereby enhancing antitumor immune responses. These synergistic therapeutic effects were validated in two hematological malignancy models, demonstrating significant tumor growth inhibition, metastasis blockade, and immune microenvironment remodeling. In summary, Pt-LNP@E5 represents a promising strategy for the development of novel platinum-based nanomedicines with broad therapeutic potential.