Framework Nucleic Acids‐Based VEGF Signaling Activating System for Angiogenesis: A Dual Stimulation Strategy

Abstract Angiogenesis is crucial for tissue engineering, wound healing, and regenerative medicine. Nanomaterials constructed based on specific goals can be employed to activate endogenous growth factor‐related signaling. In this study, based on the conventional single‐stranded DNA self‐assembly into tetrahedral framework nucleic acids (tFNAs), the Apt02 nucleic acid aptamer and dimethyloxallyl glycine (DMOG) small molecule are integrated into a complex via a template‐based click chemistry reaction and toehold‐mediated strand displacement reaction. Thus, being able to simulate the VEGF (vascular endothelial growth factor) function and stabilize HIF (hypoxia‐inducible factor), a functional whole is constructed and applied to angiogenesis. Cellular studies demonstrate that the tFNAs‐Apt02 complex (TAC) has a conspicuous affinity to human umbilical vein endothelial cells (HUVECs). Further incubation with DMOG yields the tFNAs‐Apt02‐DMOG complex (TACD), which promotes VEGF secretion, in vitro blood vessel formation, sprouting, and migration of HUVECs. Additionally, TACD enhances angiogenesis by upregulating the VEGF/VEGFR and HIF signaling pathways. Moreover, in a diabetic mouse skin defect repair process, TACD increases blood vessel formation and collagen deposition, therefore accelerating wound healing. The novel strategy simulating VEGF and stabilizing HIF promotes blood‐vessel formation in vivo and in vitro and has the potential for broad applications in the vascularization field.