Biomimetic platelet membrane-camouflaged nanomicelles for synergistic hypoxia alleviation and immune activation to potentiate immunotherapy in TNBC.

Abstract

Triple-negative breast cancer (TNBC) remains poor response to immunotherapy, largely attributable to the hypoxic tumor microenvironment that drives functional exhaustion of effector T cells and natural killer (NK) cells. To counter this, we engineered platelet-membrane-biomimetic nanomicelles (PM@(M/B)NM) for the co-delivery of metformin and BMS-1 with acid-responsive release profiles. The biomimetic nanocarriers retained characteristic platelet membrane proteins, effectively evading macrophage phagocytosis, prolonging systemic circulation, and enhancing active tumor accumulation. In vitro, exposure to acidic tumor-mimetic medium triggered accelerated drug release from PM@(M/B)NM, which substantially downregulated HIF-1α, VEGF, and GLUT1 expression while curbing reactive oxygen species (ROS) overproduction in hypoxic cancer cells. In an orthotopic TNBC murine model, the nanoplatform markedly suppressed primary tumor progression and distant lung/liver metastasis, accompanied by a significant extension of overall survival. Integrative transcriptomic-metabolomic profiling, coupled with multiplex immunofluorescence and flow cytometry, elucidated that PM@(M/B)NM orchestrated metabolic reprogramming via the HIF-1α/GLUT1/LDHA axis to alleviate hypoxia, while simultaneously diminishing immunosuppressive infiltrates and related cytokine secretion. This dual modulation synergistically revitalized the intratumoral infiltration and cytotoxic potency of CD8⁺ T cells and NK cells, thereby unleashing robust anti-tumor immunity. Collectively, our findings position PM@(M/B)NM as a safe and promising biomimetic platform to improve immunotherapy responsiveness in TNBC.