Proangiogenic Cyclic Peptide Nanotubes for Diabetic Wound Healing

An intricate biochemical system of coordinated cellular reactions is involved in restoring damaged tissue after wounds. In chronic wounds, such as diabetic foot ulcers, poor angiogenesis is a common stumbling block due to elevated glucose levels, increased proteolytic enzyme activity, and decreased production of growth factors. While various strategies, including modulation of inflammatory cells, administration of growth factors, and therapies involving stem cells or genes, have been explored to promote angiogenesis, they often suffer from limitations such as poor biodistribution, immunological rejection, administration/dosing, and proteolytic instability. Glycosaminoglycans, such as heparan sulfate, facilitate growth factor interactions with their receptors to induce angiogenic signaling, but their exogenous administration is hindered by poor stability, low serum half-life, and immunogenicity. Cyclic peptides, known for their structural stability and specificity, offer a promising alternative for inducing angiogenesis upon functional modifications. In this work, we developed heparan sulfate (HS)-mimetic cyclic peptide nanotubes (CPNTs) grafted with bioactive groups to enhance angiogenesis without using exogenous growth factors, drugs, or supplements. These CPNTs incorporate glutamic acid, serine, and sulfonated lysine to mimic the functional groups in heparin. The sulfonated cyclic hexapeptide nanotubes developed from ^DPro-^LTrp-^DLeu-^LSer-^DGlu-^LLys demonstrated significant proangiogenic activity in HUVECs under hyperglycemic conditions; enhanced endothelial cell motility, invasion, and tube formation; and upregulation of proangiogenic genes and proteins. These HS-mimicking nanotubes have shown a strong potential for promoting impaired angiogenesis, without incorporating exogenous growth factors, and show strong potential in treating diabetic wounds. To the best of our knowledge, this is the first report on the use of HS-mimetic proangiogenic cyclic peptide nanotubes for diabetic wound healing.