Multifunctional ZIF-91-Based GelMA Hydrogel Microneedles Patch with Antibacterial and Anti-Inflammatory Effects for Diabetic Wound Healing

Diabetic wound healing is a global biomedical challenge. Bacterial infection and microenvironmental modulation are major factors in the refractory healing of diabetic wounds. Conventional therapeutic approaches are often hindered by limitations, such as inadequate drug penetration, the rise of antimicrobial resistance, and restricted depth of drug delivery. Nanomedicine is emerging as a prospective drug delivery and anti-infective therapeutic approach in the field of wound management. Herein, all-trans retinoic acid (ATRA) was loaded into a zeolite imidazolate framework-91 salt+ (ZIF-91 salt+). A gelatin methacryloyl (GelMA) hydrogel microneedles (MNs) patch based on this multifunctional ZIFs (denoted as GelMA-ZIF-91 salt+@ATRA MNs patch) was developed, which makes transdermal drug delivery and combinatory treatment for diabetic wound healing feasible. Significantly, ATRA-containing ZIF-91 salt+ provides nanocomposites with anti-inflammatory activity through their modulation of macrophage polarization. Crucially, the prepared ZIF-91 salt+ showed efficient antibacterial activity against Staphylococcus aureus and Escherichia coli in vitro. Therapeutic effects of the GelMA-ZIF-91 salt+@ATRA MNs patch were verified in a diabetic mouse model with full-thickness cutaneous wounds. A unique MNs patch with antimicrobial, angiogenesis-inducing, and anti-inflammatory properties was designed in accordance with the physiological characteristics of wounds. Collectively, the designed MNs patch based on this multifunctional ZIF-91 salt+ provides new insights into diabetic wound therapy.

糖尿病创面愈合是一项全球性生物医学挑战。细菌感染与微环境调控异常是糖尿病创面难愈的核心诱因。常规治疗手段常受限于诸多缺陷，如药物渗透不足、抗菌药物耐药性攀升以及给药深度受限。纳米医学正逐渐成为创面管理领域极具前景的给药与抗感染治疗策略。本研究将全反式维甲酸（all-trans retinoic acid, ATRA）负载至沸石咪唑酯骨架材料-91盐+（zeolite imidazolate framework-91 salt+, ZIF-91盐+）中，开发出基于该多功能沸石咪唑酯骨架材料的甲基丙烯酸明胶（gelatin methacryloyl, GelMA）水凝胶微针（hydrogel microneedles, MNs）贴片（命名为GelMA-ZIF-91盐+@ATRA MNs贴片），使经皮给药与糖尿病创面愈合联合治疗成为可能。值得注意的是，负载ATRA的ZIF-91盐+可通过调控巨噬细胞极化赋予纳米复合物抗炎活性。尤为关键的是，所制备的ZIF-91盐+在体外对金黄色葡萄球菌与大肠埃希菌均表现出高效抗菌活性。本研究在糖尿病小鼠全层皮肤创面模型中验证了该GelMA-ZIF-91盐+@ATRA MNs贴片的治疗效果。该微针贴片贴合创面生理特征，兼具抗菌、促血管生成与抗炎三重特性，综上，本研究开发的基于多功能ZIF-91盐+的微针贴片为糖尿病创面治疗提供了全新思路。