Nanoparticles reach metastatic tumours via enhanced permeability of adjacent vessels

Considering that 90% of cancer-related deaths are due to metastasis, treating micrometastases in their infancy is critical. Targeting micrometastases with nanoparticles has shown therapeutic potential, but a limited understanding of the delivery mechanisms has slowed material optimization. Here, using real-time intravital imaging, we discover that nanoparticles can gather around avascular micrometastases through the enhanced permeability of vessels in adjacent non-malignant tissues, defined as the enhanced permeability of adjacent vessels effect. We show that micrometastases have altered mechanical properties and imposed compressive stress on adjacent vessels, activating β1 integrins and subsequent cytoskeletal organization, which leads to the disruption of endothelial integrity and increased vascular permeability. Ultimately, this enhanced-permeability-of-adjacent-vessels-enabled nanoparticle enrichment substantially amplifies the therapeutic outcomes for metastatic interventions. These findings elucidate the mechanisms of nanoparticle delivery to micrometastases, offering promising avenues for nanoparticle-based diagnostics and therapies for metastatic cancer.