Targeting VEGFR2 inhibition within a spatially-confined conduit promotes nerve self-resolution and alleviates mechanical allodynia.

Abstract

Stump neuromas represent nonfunctional redundant tissue that frequently elicits neuropathic pain through disorganized axonal regeneration, pathological angiogenesis, scar hyperplasia, and chronic neuroinflammation. Current therapeutic strategies fail to adequately address the underlying pathophysiology, particularly the excessive production of reactive oxygen species resulting from dysregulated vascular proliferation and activation. To tackle this issue, we developed photo-crosslinked gelatin methacryloyl (GelMA) microspheres covalently functionalized with methacryloyl-modified anti-VEGFR2 peptides (MAVP) to modulate pathological angiogenesis. These functionalized microspheres were fabricated into linear arrays via 3D printing and integrated within a progressively spatial-constrictive conduit. This platform facilitated the self-resolution of the nerve end interface, including sustained suppression of VEGFR2 phosphorylation and coordinated mechanotransduction signaling, thereby inhibiting neuroinflammatory responses and angiogenesis. In a sciatic nerve ligation model, GelMA^MAVP MPs system demonstrated markedly superior analgesic efficacy over the conventional VEGFR2 inhibitor vandetanib. In a stump neuroma model, GelMA^MAVP MPs effectively normalized the peripheral end interface microenvironment by inhibiting neovascularization, M1 macrophage polarization, and fibrotic scar formation. Furthermore, GelMA^MAVP MPs distributed in the peripheral nerve stumps indirectly downregulated pain-related proteins (TRPA1/CGRP) in dorsal root ganglia and suppressed spinal microglial activation. Overall, this study presents a comprehensive and safe vascular-targeted strategy promoting nerve end interface self-resolution and prevention of neuropathic pain.