Programming angiogenesis with tunable assemblies of multifunctional peptides.

Abstract

Therapeutic angiogenesis is constrained by the inability to localize, sustain, and finely tune vascular signaling. Here, we detail a supramolecular peptide system that enables angiogenic programming by decoupling mechanical integrity from receptor-level bioactivity. We integrate a vascular endothelial growth factor (VEGF)-mimetic amphiphile (SLan) with a mechanically robust β sheet peptide (K1) to yield injectable nanofiber hydrogels with tunable stiffness (100 to 1000 pascals) and preserved vascular endothelial growth factor receptor 2 (VEGFR2) affinity. Molecular dynamics simulations and solid-state nuclear magnetic resonance revealed that the coassembly mitigates steric interference between domains, enabling dense supramolecular packing while maintaining optimal receptor accessibility. The resulting SLan-K1 formulation preserves the secondary structure, activating canonical VEGFR2-MEK (mitogen-activated protein kinase kinase)-ERK (extracellular signal-regulated kinase). In vitro, these hydrogels induce endothelial proliferation; in vivo, they drive rapid neovascular infiltration and stable vascular integration in murine and rodent implants. This design unites peptide self-assembly, receptor binding kinetics, and immunophenotypic outcomes in defining a molecular framework for tunable angiogenic materials. This strategy establishes a modular platform for engineering instructive microenvironments that bridge molecular design and tissue-scale functionality.