Abstract
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(2)@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(2)@HIF-1α nanomotor. Due to the good antioxidant activity of PDA, PDA@MS-NH(2)@HIF-1α nanomotors exhibit exceptional biocompatibility and significantly enhance the ischemic microenvironment. In vitro and in vivo outcomes verify that PDA@MS-NH(2)@HIF-1α nanomotors have enhanced pro-angiogenic capacity and improved gene transfection efficiency. Furthermore, the therapeutic efficacy of PDA@MS-NH(2)@HIF-1α is assessed using a murine hindlimb ischemia model. The results show that the intramuscular injection of PDA@MS-NH(2)@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.