Gao Qian, Hu Fangfang, Chai Zihan, Zheng Caiyun, Zhang Wenhui, Pu Ke, Yang Ziyi, Zhang Yanni, Ramrkrishna Seeram, Wu Xianglong, Lu Tingli
Key Laboratory of Space Bioscience and Biotechnology, Engineering Research Center of Chinese Ministry of Education for Biological Diagnosis, Treatment and Protection Technology and Equipment, School of Life Sciences, Northwestern Polytechnical University, No. 1 Dongxiang Road, Chang'an District, Xi'an City, 710129, People's Republic of China.
Department of Mechanical Engineering, College of Design and Engineering, National University of Singapore, 21 Lower Kent Ridge Road, Singapore, 117574, Singapore.
J Nanobiotechnology. 2025 May 26;23(1):380. doi: 10.1186/s12951-025-03451-6.
Diabetic wound infections, exacerbated by multidrug-resistant pathogens like MRSA, remain a critical challenge due to biofilm persistence and dysregulated oxidative-inflammatory-metabolic crosstalk.
In this work, we engineered COG-Z@P200 hydrogel, a chitosan-based hydrogel integrating polydopamine-coated ZIF-8 nanoparticles, to synergize mild photothermal therapy (40-45 °C) with metabolic-immune reprogramming. Upon NIR irradiation, COG-Z@P200 disrupted MRSA through Zn⁺-mediated membrane destabilization and localized hyperthermia, achieving >99.5% eradication via combined physical puncture and metabolic interference. Multi-omics analyses revealed suppression of glycolysis (eno, gap downregulation), TCA cycle arrested (sucC, sdhA, icd inhibition), and disruption of arginine biosynthesis (arcA, arcC, arcD downregulation), impairing biofilm formation and pathogenicity. Concurrent silencing of quorum sensing and virulence genes (agr, sec, lac, opp, sdrD) further destabilized MRSA, while upregulation of stress-response genes (yidD, nfsA, kdpA) indicated bacterial metabolic paralysis. In diabetic murine models, the hydrogel attenuated oxidative stress (DHE-confirmed ROS reduction), polarized macrophages to pro-healing M2 phenotypes (Arg-1⁺/TNF-α↓), and enhanced angiogenesis (VEGF/CD31↑) alongside aligned collagen deposition. This multifunctional action accelerated wound closure by 48% versus controls, outperforming clinical standards. By converging nanomaterial-enabled bactericidal strategies with host microenvironment recalibration, COG-Z@P200 hydrogel redefined diabetic wound management, offering an antibiotic-free solution against multidrug-resistant infections.
Our work established a biomaterial paradigm that concurrently targets pathogen vulnerabilities and restores tissue homeostasis, addressing the multidimensional complexity of chronic wounds.
糖尿病伤口感染因耐多药病原体（如耐甲氧西林金黄色葡萄球菌）而加剧，由于生物膜的持续存在以及氧化-炎症-代谢串扰失调，仍然是一个严峻的挑战。
在这项工作中，我们设计了COG-Z@P200水凝胶，这是一种基于壳聚糖的水凝胶，整合了聚多巴胺包覆的ZIF-8纳米颗粒，以将温和的光热疗法（40-45°C）与代谢-免疫重编程协同作用。在近红外照射下，COG-Z@P200通过锌离子介导的膜不稳定和局部热疗破坏耐甲氧西林金黄色葡萄球菌，通过联合物理穿刺和代谢干扰实现>99.5%的根除率。多组学分析显示糖酵解受到抑制（烯醇酶、甘油醛-3-磷酸脱氢酶下调），三羧酸循环停滞（琥珀酸辅酶A合成酶、琥珀酸脱氢酶、异柠檬酸脱氢酶受到抑制），精氨酸生物合成受到破坏（精氨酸转运蛋白A、精氨酸转运蛋白C、精氨酸转运蛋白D下调），损害生物膜形成和致病性。群体感应和毒力基因（葡萄球菌A蛋白、分泌蛋白、乳糖蛋白、寡肽转运蛋白、表面蛋白D）的同时沉默进一步破坏了耐甲氧西林金黄色葡萄球菌的稳定性，而应激反应基因（YidD、NfsA、KdpA）的上调表明细菌代谢麻痹。在糖尿病小鼠模型中，水凝胶减轻了氧化应激（二氢乙啶证实活性氧减少），将巨噬细胞极化为促愈合的M2表型（精氨酸酶-1阳性/肿瘤坏死因子-α下降），并增强了血管生成（血管内皮生长因子/血小板内皮细胞黏附分子-1升高），同时胶原沉积排列整齐。这种多功能作用使伤口闭合速度比对照组加快了48%，优于临床标准。通过将纳米材料介导的杀菌策略与宿主微环境重新校准相结合，COG-Z@P200水凝胶重新定义了糖尿病伤口管理，提供了一种针对耐多药感染的无抗生素解决方案。
我们的工作建立了一种生物材料范式，同时针对病原体的脆弱性并恢复组织内稳态，解决了慢性伤口的多维度复杂性。
