Injectable aptamer-functionalized nucleic acid-collagen hydrogels as a bioactive platform for angiogenic applications

Abstract

Nucleic acid-collagen complexes (NACCs) have gained prominence as multifunctional biomaterials fabricated by the self-assembly of type I collagen and single-stranded DNA (ssDNA). This study reports injectable NACCs functionalized with an ssDNA aptamer that activates the vascular endothelial growth factor receptor 2 (VEGFR-2), organizing into a hydrogel capable of promoting localized angiogenesis. The protection of the embedded aptamer from degradation was confirmed under nuclease-rich conditions, and rheological analysis demonstrated the shear-thinning behavior of the hydrogel, supporting injectability through a 25G needle. In vitro, NACCs facilitated endothelial cell attachment, spreading, proliferation, and the formation of early vascular-like structures when embedded within the matrix (three-dimensional culture). In vivo, subcutaneously injected VEGFR-2-aptamer-NACCs in mice led to host cell infiltration, structural remodeling, and the formation of new blood vessels without the need for exogenous growth factors or cell transplant. Plasma collected from implanted mice showed low or undetectable cytokine levels, indicating minimal systemic inflammation and confirming the platform's biocompatibility. Collectively, these findings establish ssDNA aptamer-containing NACCs as a bioactive and translationally relevant hydrogel platform capable of supporting pro-angiogenic remodeling for regenerative medicine applications.

Keywords: Bioactive hydrogel; DNA-collagen complexes; Endothelial cells; Tunable biomaterials; VEGFR-2 agonist aptamer; Vasculogenesis.