Gui Liang, Wang Suyu, Miao Suyu, Qiao Minghang, Jiao Yuanyong, Chen Haibin, Li WanYang, Zou Junjie, Du Xin
Department of Vascular Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, China.
Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, China.
Mater Today Bio. 2025 Jun 6;33:101950. doi: 10.1016/j.mtbio.2025.101950. eCollection 2025 Aug.
Among multiple non-invasive therapeutic approaches for critical limb ischemia (CLI), gene therapy has been widely researched because of its capacity to ensure continuous expression and growth factors release. Hypoxia-inducible factor-1α (HIF-1α), a gene that can promote stable angiogenesis and tissue restoration, is a potential candidate for facilitating cellular adaptation to hypoxia during vascular injury recovery. Herein, we designed a near-infrared (NIR) light-propelled pEX-1/HIF-1α plasmid DNA (pDNA) loaded Janus polydopamine@mesoporous silica (PDA@MS) nanomotors (PDA@MS-NH@HIF-1α) with asymmetric yolk@shell structure and rough particle surface containing large pores. The PDA@MS nanomotors have a rough and porous particle surface that is modified with positively charged aminopropyl. This modification enables efficient electrostatic absorption of negatively charged pDNA, resulting in a high loading capacity. The distribution of yolk in the asymmetric PDA enables the creation of a localized thermal gradient field around the PDA@MS when exposed to irradiation with a low-energy-intensity NIR laser. This allows the PDA@MS to move via a self-thermophoretic mechanism. The NIR light propulsion promotes the efficient delivery of HIF-1α-pDNA by PDA@MS-NH@HIF-1α nanomotor. Due to the good antioxidant activity of PDA, PDA@MS-NH@HIF-1α nanomotors exhibit exceptional biocompatibility and significantly enhance the ischemic microenvironment. In vitro and in vivo outcomes verify that PDA@MS-NH@HIF-1α nanomotors have enhanced pro-angiogenic capacity and improved gene transfection efficiency. Furthermore, the therapeutic efficacy of PDA@MS-NH@HIF-1α is assessed using a murine hindlimb ischemia model. The results show that the intramuscular injection of PDA@MS-NH@HIF-1α combined with NIR light irradiation leads to a significant improvement in blood flow restoration and muscle repair. When considering these findings collectively, this kind of gene-delivery nanomotor has the potential to be a promising paradigm for future CLI treatment.
在治疗严重肢体缺血（CLI）的多种非侵入性治疗方法中，基因治疗因其能够确保持续表达和生长因子释放而受到广泛研究。缺氧诱导因子-1α（HIF-1α）是一种能够促进稳定血管生成和组织修复的基因，是在血管损伤恢复过程中促进细胞适应缺氧的潜在候选基因。在此，我们设计了一种近红外（NIR）光驱动的负载pEX-1/HIF-1α质粒DNA（pDNA）的Janus聚多巴胺@介孔二氧化硅（PDA@MS）纳米马达（PDA@MS-NH@HIF-1α），其具有不对称的蛋黄@壳结构和含有大孔的粗糙颗粒表面。PDA@MS纳米马达具有粗糙且多孔的颗粒表面，该表面用带正电荷的氨丙基进行了修饰。这种修饰能够有效地静电吸附带负电荷的pDNA，从而具有高负载能力。不对称PDA中蛋黄的分布使得在低能量强度近红外激光照射下，PDA@MS周围能够产生局部热梯度场。这使得PDA@MS能够通过自热泳机制移动。近红外光推进促进了PDA@MS-NH@HIF-1α纳米马达对HIF-1α-pDNA的高效递送。由于PDA具有良好的抗氧化活性，PDA@MS-NH@HIF-1α纳米马达表现出优异的生物相容性，并显著改善缺血微环境。体外和体内实验结果证实，PDA@MS-NH@HIF-1α纳米马达具有增强的促血管生成能力和提高的基因转染效率。此外，使用小鼠后肢缺血模型评估了PDA@MS-NH@HIF-1α的治疗效果。结果表明，肌肉注射PDA@MS-NH@HIF-1α并结合近红外光照射可显著改善血流恢复和肌肉修复。综合考虑这些发现，这种基因递送纳米马达有可能成为未来CLI治疗的一种有前景的范例。
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