Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, China.
University Hunan Engineering Research Center of Biomedical Metal and Ceramic Implants, Xiangya Hospital, Central South University, Changsha, China.
J Nanobiotechnology. 2024 Apr 4;22(1):152. doi: 10.1186/s12951-024-02398-4.
Infected wound healing remains a challenging task in clinical practice due to several factors: (I) drug-resistant infections caused by various pathogens, (II) persistent inflammation that hinders tissue regeneration and (III) the ability of pathogens to persist intracellularly and evade antibiotic treatment. Microneedle patches (MNs), recognized for their effecacious and painless subcutaneous drug delivery, could greatly enhance wound healing if integrated with antibacterial functionality and tissue regenerative potential. A multifunctional agent with subcellular targeting capability and contained novel antibacterial components, upon loading onto MNs, could yield excellent therapeutic effects on wound infections. In this study, we sythesised a zeolitic imidazolate framework-8 nanoparticles (ZIF-8 NPs) loaded with low molecular weight fucoidan (Fu) and further coating by hyaluronic acid (HA), obtained a multifunctional HAZ@Fu NPs, which could hinders Methicillin-resistant Staphylococcus aureus (MRSA) growth and promotes M2 polarization in macrophages. We mixed HAZ@Fu NPs with photocrosslinked gelatin methacryloyl (GelMA) and loaded it into the tips of the MNs (HAZ@Fu MNs), administered to mice model with MRSA-infected full-thickness cutaneous wounds. MNs are able to penetrate the skin barrier, delivering HAZ@Fu NPs into the dermal layer. Since cells within infected tissues extensively express the HA receptor CD44, we also confirmed the HA endows the nanoparticles with the ability to target MRSA in subcellular level. In vitro and in vivo murine studies have demonstrated that MNs are capable of delivering HAZ@Fu NPs deep into the dermal layers. And facilitated by the HA coating, HAZ@Fu NPs could target MRSA surviving at the subcellular level. The effective components, such as zinc ions, Fu, and hyaluronic acid could sustainably released, which contributes to antibacterial activity, mitigates inflammation, promotes epithelial regeneration and fosters neovascularization. Through the RNA sequencing of macrophages post co-culture with HAZ@Fu, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis reveals that the biological functionalities associated with wound healing could potentially be facilitated through the PI3K-Akt pathway. The results indicate that the synergistic application of HAZ@Fu NPs with biodegradable MNs may serve as a significant adjunct in the treatment of infected wounds. The intricate mechanisms driving its biological effects merit further investigation.
由于以下几个因素，感染性伤口的愈合仍然是临床实践中的一个挑战：（I）各种病原体引起的耐药性感染，（II）持续的炎症阻碍组织再生，以及（III）病原体在细胞内持续存在并逃避抗生素治疗的能力。微针贴片（MNs）因其有效的、无痛的皮下药物输送而得到认可，如果与抗菌功能和组织再生潜力相结合，将极大地促进伤口愈合。一种具有亚细胞靶向能力和包含新型抗菌成分的多功能药物，如果负载到 MNs 上，可能对伤口感染产生极好的治疗效果。在这项研究中，我们合成了负载低分子量岩藻聚糖（Fu）的沸石咪唑酯骨架-8 纳米颗粒（ZIF-8 NPs），并进一步用透明质酸（HA）包被，得到了一种多功能的 HAZ@Fu NPs，它可以抑制耐甲氧西林金黄色葡萄球菌（MRSA）的生长并促进巨噬细胞中 M2 极化。我们将 HAZ@Fu NPs 与光交联的明胶甲基丙烯酰（GelMA）混合，并将其装载到 MNs 的尖端（HAZ@Fu MNs）中，然后将其施用于 MRSA 感染的全层皮肤伤口的小鼠模型中。MNs 能够穿透皮肤屏障，将 HAZ@Fu NPs 递送到真皮层。由于感染组织中的细胞广泛表达 HA 受体 CD44，我们还证实了 HA 赋予纳米颗粒在亚细胞水平靶向 MRSA 的能力。体外和体内小鼠研究表明，MNs 能够将 HAZ@Fu NPs 递送到真皮层深处。并且，由于 HA 涂层的存在，HAZ@Fu NPs 可以靶向亚细胞水平存活的 MRSA。有效成分，如锌离子、Fu 和透明质酸，可持续释放，有助于发挥抗菌活性、减轻炎症、促进上皮再生和促进新血管生成。通过与 HAZ@Fu 共培养后的巨噬细胞的 RNA 测序，京都基因与基因组百科全书（KEGG）途径分析显示，与伤口愈合相关的生物功能可能通过 PI3K-Akt 途径得到促进。结果表明，HAZ@Fu NPs 与可生物降解的 MNs 的协同应用可能成为治疗感染性伤口的重要辅助手段。其驱动生物学效应的复杂机制值得进一步研究。
