Ultrasound-Controlled Nano-Oxygen Delivery Modulates Endothelial Cells to Enhance Tumor Perfusion

The concept of vascular normalization represents a promising
strategy
for antitumor therapy. However, clinical translation of antiangiogenic
agents to induce and sustain tumor vascular normalization remains
hampered by acquired drug tolerance and dose-limiting systemic toxicities.
Here, we demonstrate that focused ultrasound-stimulating oxygen nanobubbles
(ONB_FUS) can effectively alleviate tumor hypoxia and drive vascular
normalization, evidenced by improved intratumoral perfusion, reduced
microvascular density, and increased pericyte coverage. During this
normalization window, key proangiogenic signaling pathways, including
VEGFA and ANGPT2, were significantly downregulated. Single-cell RNA
sequencing of tumor endothelial cells (TECs) identified capillary
endothelial cells (CapECs) as the primary responsive population, with
selective depletion of the proangiogenic CapEC_Spp1+ subset.
Clinical tumor samples corroborated these findings, showing elevated
CapEC abundance and heightened ANGPT/VEGF pathway activity, specifically
in high-proliferation CapECs. Functionally, ONB_FUS-mediated vascular
repriming significantly enhanced intratumoral drug delivery and potentiated
chemotherapy efficacy. Collectively, ONB_FUS offers a spatiotemporally
controllable approach to vascular remodeling that complements standard-of-care
therapeutics. Moreover, the identification of functionally distinct
TEC subpopulations reveals mechanistically guided targets for precision
antiangiogenic intervention.