Supramolecular peptide hydrogel doped with nanoparticles for local siRNA delivery and diabetic wound healing

High expression of matrix metalloproteinase 9 (MMP-9) has been demonstrated to significantly impair the healing of diabetic wounds. Three-dimensional hydrogels have been widely used for local siRNA delivery and wound healing via silencing MMP-9 expression. However, the negatively charged nature of siRNA released from the hydrogel dramatically weakens the cellular uptake of siRNA, thereby inducing suboptimal therapeutic outcomes. To address this issue, we herein developed a supramolecular peptide hydrogel doped with nanoparticles (NPs) for local MMP-9 siRNA (siMMP-9) delivery and diabetic wound healing. For this siRNA delivery system, siMMP-9 was encapsulated into NPs made with an amphiphilic cationic lipid-like compound and then embedded into a supramolecular peptide hydrogel self-assembled from an amphiphilic peptide. After administration to the diabetic wounds as dressing, the peptide hydrogel could not only dramatically prolong the retention of siRNA-loaded NPs at the wound tissues, but also gradually release the siRNA-loaded NPs from its porous network to improve the siRNA uptake by keratinocytes, leading to efficient MMP-9 silencing and significant improvement of diabetic wound healing. The siRNA delivery system developed in this work could be used as an effective tool to regulate the expression of other diabetic wound-associated genes and improve the diabetic wound healing.