Capturing the RNA castle: Exploiting MicroRNA inhibition for wound healing

The growing pipelines of RNA‐based therapies herald new opportunities to deliver better patient outcomes for complex disorders such as chronic nonhealing wounds associated with diabetes. Members of the microRNA (miRNA) family of small noncoding RNAs have emerged as targets for diverse elements of cutaneous wound repair, and both miRNA enhancement with mimics or inhibition with antisense oligonucleotides represent tractable approaches for miRNA‐directed wound healing. In this review, we focus on miRNA inhibition strategies to stimulate skin repair given advances in chemical modifications to enhance the performance of antisense miRNA (anti‐miRs). We first explore miRNAs whose inhibition in keratinocytes promotes keratinocyte migration, an essential part of re‐epithelialisation during wound repair. We then focus on miRNAs that can be targeted for inhibition in endothelial cells to promote neovascularisation for wound healing in the context of diabetic mouse models. The picture that emerges is that direct comparisons of different anti‐miRNAs modifications are required to establish the most translationally viable options in the chronic wound environment, that direct comparisons of the impact of inhibition of different miRNAs are needed to quantify and rank their relative efficacies in promoting wound repair, and that a standardised human ex vivo model of the diabetic wound is needed to reduce reliance on mouse models that do not necessarily enhance mechanistic understanding of miRNA‐targeted wound healing. Chronic wounds are on the rise. Many microRNAs (miRNA) are dysregulated in such wounds. We therefore explore miRNAs whose inhibition can support wound healing. Such approaches can target epidermal keratinocytes, promoting the migration of these cells during wound repair. Alternatively, miRNAs can be blocked in endothelial cells, facilitating wound healing through neovascularisation. Chemical modifications that enhance the performance of anti‐miRNA oligonucleotides are also considered.