Metal-organic framework-based Z-scheme heterostructure enables oxygen-independent sonodynamic immunotherapy through tumor-associated macrophage reprogramming.

Sonodynamic therapy (SDT) provides spatially controlled tumor treatment, but its efficacy in hypoxic tumors is limited by oxygen-dependent reactive oxygen species (ROS) generation and tumor-associated macrophage (TAM)-mediated immunosuppression. Here, we developed a hyaluronic acid (HA)-modified, metal-organic framework (MOF)-based CuO₂@FeTCPP Z-scheme nanosonosensitizer to combine hypoxia-tolerant hydroxyl radical (•OH) generation with macrophage reprogramming. Band-edge analysis, interfacial X-ray photoelectron spectroscopy, and spin-trapping and scavenging experiments provided complementary support for a Z-scheme charge-transfer pathway that preserves reducing electrons on FeTCPP and highly oxidative holes on CuO₂. Under ultrasound irradiation, CuO₂@FeTCPP@HA maintained strong •OH generation under hypoxia, whereas oxygen-dependent 1O₂ production was substantially attenuated. HA modification enhanced CD44-associated cellular uptake, as demonstrated by comparison with the HA-free material and by CD44-blocking experiments. In M2-like macrophages, CuO₂@FeTCPP@HA treatment without ultrasound was accompanied by increased H3 acetylation and decreased H3K9 trimethylation, whereas ultrasound activation markedly increased •OH production and amplified the M2-to-M1 phenotypic and cytokine responses. These observations support distinct but convergent contributions from Cu-associated metabolic-epigenetic regulation and ultrasound-triggered oxidative stress. In a bilateral subcutaneous A20 lymphoma model, local treatment of the primary tumor suppressed both irradiated primary and non-irradiated contralateral tumors, reduced the bone marrow lymphoma burden, and promoted dendritic cell maturation, CD8+ T-cell infiltration, and effector memory T-cell formation. Together, these results demonstrate a materials-based strategy that integrates oxygen-independent sonocatalysis with macrophage-centered immune remodeling for systemic antitumor therapy.