Hydroxyapatite-mineralized metal-organic frameworks as sonosensitizer modulate tumor microenvironment to potentiate high-intensity focused ultrasound therapy.

High-intensity focused ultrasound (HIFU) has emerged as a game-changing breast-conserving therapeutic modality owing to its dual functions of non-invasive tumor ablation and immunity activation. However, its low focal gain in the target region results in residual tumor tissue after ablation. Inspired by the exceptional acoustic response of bone tumor to HIFU, we developed bone-derived hydroxyapatite (HA)-mineralized metal-organic frameworks (designated as AZSH MOFs) as sonosensitizer that co-encapsulated Zn2+, hypoxic-activated prodrug AQ4N, and STING agonist SR-717 for acoustic-immunological synergistic therapy. AZSH MOFs enabled targeted delivery of HA to mimic bone tumor-like acoustic environment, markedly amplified HIFU energy deposition in the breast tumor tissue, and thus achieved more thorough ablation and local hypoxic. The exacerbated hypoxic selectively activated AQ4N to trigger immunogenic cell death. Meanwhile, Zn2+ with SR-717 upregulated stimulator of interferon genes (STING) pathway to promote intratumoral infiltration of immune cells, and ultimately relieved the immunosuppressive tumor microenvironment. Thus, AZSH MOFs not only improve ablation efficiency of HIFU but also treat residual tumor via enhanced multilevel immune activation, offering valuable insights to facilitate the extensive clinical application of HIFU technology.