Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60603, USA; Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Department of Vascular Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang 310058, China.
Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA; Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53715, USA.
J Control Release. 2024 Dec;376:806-815. doi: 10.1016/j.jconrel.2024.10.045. Epub 2024 Nov 1.
Endovascular interventions often fail due to restenosis, primarily caused by smooth muscle cell (SMC) proliferation, leading to intimal hyperplasia (IH). Current strategies to prevent restenosis are far from perfect and impose significant collateral damage on the fragile endothelial cell (EC), causing profound thrombotic risks. Nicotinamide adenine dinucleotide (NAD) is a co-enzyme and signaling substrate implicated in redox and metabolic homeostasis, with a pleiotropic role in protecting against cardiovascular diseases. However, a functional link between NAD repletion and the delicate duo of IH and EC regeneration has yet to be established. NAD repletion has been historically challenging due to its poor cellular uptake and low bioavailability. We have recently invented the first nanocarrier that enables direct intracellular delivery of NAD in vivo. Combining the merits of this prototypic NAD-loaded calcium phosphate (CaP) nanoparticle (NP) and biomimetic surface functionalization, we created a biomimetic P-NAD-NP with platelet membrane coating, which enabled an injectable modality that targets IH with excellent biocompatibility. Using human cell primary culture, we demonstrated the benefits of NP-assisted NAD repletion in selectively inhibiting the excessive proliferation of aortic SMC, while differentially protecting aortic EC from apoptosis. Moreover, in a rat balloon angioplasty model, a single-dose treatment with intravenously injected P-NAD-NP immediately post angioplasty not only mitigated IH, but also accelerated the regeneration of EC (re-endothelialization) in vivo in comparison to control groups (i.e., saline, free NAD solution, empty CaP-NP). Collectively, our current study provides proof-of-concept evidence supporting the role of targeted NAD repletion nanotherapy in managing restenosis and improving reendothelialization.
血管内介入治疗常常由于再狭窄而失败，再狭窄主要是由平滑肌细胞（SMC）增殖引起的，导致内膜增生（IH）。目前预防再狭窄的策略远非完美，会对脆弱的内皮细胞（EC）造成严重的附带损伤，导致严重的血栓形成风险。烟酰胺腺嘌呤二核苷酸（NAD）是一种辅酶和信号底物，参与氧化还原和代谢稳态，在预防心血管疾病方面具有多种作用。然而，NAD 补充与 IH 和 EC 再生这对微妙组合之间的功能联系尚未建立。由于 NAD 的细胞摄取能力差和生物利用度低，其补充在历史上一直具有挑战性。我们最近发明了第一种纳米载体，可实现 NAD 在体内的直接细胞内递药。结合这种原型 NAD 负载的磷酸钙（CaP）纳米颗粒（NP）和仿生表面功能化的优点，我们创建了一种具有血小板膜涂层的仿生 P-NAD-NP，可实现针对 IH 的可注射方式，具有极好的生物相容性。使用人原代细胞培养，我们证明了 NP 辅助 NAD 补充在选择性抑制主动脉 SMC 过度增殖方面的益处，同时使主动脉 EC 免受凋亡的影响。此外，在大鼠球囊血管成形术模型中，在血管成形术后立即静脉注射 P-NAD-NP 的单次剂量治疗不仅减轻了 IH，而且与对照组（即生理盐水、游离 NAD 溶液、空 CaP-NP）相比，在体内加速了 EC 的再生（再内皮化）。总之，我们目前的研究提供了概念验证证据，支持靶向 NAD 补充纳米疗法在管理再狭窄和改善再内皮化方面的作用。
