Bioinspired TIMP-1 Nanoparticles Mimic Extracellular Vesicle Anti-angiogenic Activity in Ewing Sarcoma

Here, we present a bioinspired nanoplatform that reproduces the anti-angiogenic signaling of mesenchymal stromal cell-derived extracellular vesicles (EVs) by delivering the endogenous metalloproteinase inhibitor TIMP-1. Poly(methyl methacrylate) nanoparticles (NP_TIMP1) were engineered to retain TIMP-1 bioactivity, inhibit matrix metalloproteinase (MMP) activity, and selectively target endothelial cells.

In vitro, NP_TIMP1 suppressed endothelial sprouting and tip-cell formation in 2D and 3D microfluidic systems. In zebrafish patient-derived xenografts of Ewing sarcoma, NP_TIMP1 localized to tumor-associated vessels and significantly reduced vascular infiltration, reproducing the efficacy of TIMP-1-enriched EVs. In contrast, soluble TIMP-1 failed to elicit these effects, indicating that nanoparticle-mediated delivery enhances protein stability and spatial engagement with the endothelium.