A Smart Functional Microneedle, Tethered with Neuropeptide S and Tissue Inhibitor of Metalloproteinases, Promotes Skin, Vascular, and Nerve Regeneration for Chronic Diabetic Skin Wound Healing

Increased expression and activity of matrix metalloproteinases (MMPs) coupled with reduced neuropeptide secretion at the wound site significantly impair the healing of diabetic skin wounds. Neuropeptides serve as critical neuroregulators in wound healing, with neuropeptide S (NPS) being a key member of this group. However, whether NPS can enhance the healing of skin wounds remains unconfirmed in the literature. Herein, a functional NPS‐liposome microneedle (FN‐MN) system is developed for targeted, on‐demand drug delivery aimed at promoting the healing of non‐healing skin wounds. To address the elevated expression of MMPs in the wound environment, FN‐MN by incorporating the PLGLAG sequence is modified. This modification enables the tissue inhibitor of metalloproteinases (TIMP) within the FN‐MN to specifically target and inhibit the activity of overexpressed MMPs at the injury site. Upon transplantation of FN‐MN into the skin defect region of type‐2 diabetic mice, the system demonstrates the ability to dynamically and responsively release NPS and TIMP as needed at the lesion. An full‐thickness skin regeneration, enhanced angiogenesis, and functional recovery of both autonomic and sensory nerves are observed. In conclusion, a smart functional microneedle system, tethered with NPS and TIMP, which not only promotes diabetic wound healing and tissue remodeling at the site of injury but also offers a potential therapeutic approach for clinical translation.