血管移植物（也称为血管支架）一直是临床有效的治疗血管疾病或暴力侵袭引起的大血管缺损的策略[ 4,79,80]，如聚氨酯（PU）[81 ]、聚酯（PET）[ 82 ]、ePTFE [ 83 ] 等。虽然这些血管移植物在用于大直径血管 (>6 mm) 时显示出令人满意的长期性能，但它们在小直径血管 (<6 mm) 中表现出较差的性能，主要是因为它们容易发生内膜增生 (IH) 和血栓形成 [ 84]。鉴于上述不理想的因素以及不可降解性导致二次手术的缺点，寻求生物相容性更好的天然材料来构建血管移植物一直是一个目标。不幸的是，天然材料的许多特性不能满足血管移植物的应用要求，例如机械强度 [ 85 ]、弹性 [ 16 ] 和降解 [ 86 , 87 ]。MNPs 被认为可以有效提高血管移植物的性能，并在其他领域提供更多应用（例如 MRI [ 43 ] 或纳米修饰 [ 88 ]）。戈尔巴尼等人。[ 89]通过共沉淀技术合成了INOPs，它们均匀分布在PLGA-明胶支架中。结果表明，添加的MNPs对孔形貌无特殊影响，但略微降低了孔径分布。含有该结构的MNPs具有增强的机械强度，但吸收能力和生物降解率降低。我们之前的研究 [ 16 ] 也证明了 MNPs 通过浸润均匀分布在丝素蛋白支架中。结果表明，所获得的磁性丝素蛋白支架显着延缓了降解速率，增强了机械强度。莱卡库等人。[ 90] 发现明胶/弹性蛋白凝胶是纳米复合支架，其扁平的弹性蛋白纳米域嵌入明胶基质中，模拟动脉介质的结构。他们研究了明胶/“羟基磷灰石”（HA）纳米复合材料支架，并在溶液中原位生成了“HA”。当施加9.4 T的磁场时，明胶中的HA颗粒和明胶微纤维的取向垂直于磁场方向，为制备动脉血管层状支架提供了基础。默滕斯等人。[ 20] 制备了三个超小的超顺磁性氧化铁纳米粒子（USPIO），随后通过化学交联将其直接定植在胶原支架中，并间接用作成像移植支架。在无细胞植入物的情况下也可以进行成像，以可视化胶原支架在体内的降解，这有利于分析体内降解周期和快速降解天然材料的机制。目前，添加MNP的血管移植物主要用于提高机械强度，主要是基于高模量、丰富的官能团。和 MNP 的均匀分散 [ 91 ]。

血管损伤修复是一项高度组织化的工程，主要涉及炎症、新内膜和重塑三个阶段[ 10 ]。对于初期的急性炎症阶段，许多巨噬细胞会迁移到损伤部位，分泌各种炎症因子（如TNF-α、IL-6、MCP-1），清除受损细胞碎片，起到防御作用。当进入炎症晚期并过渡到新内膜阶段（活性再内皮化阶段）时，巨噬细胞分泌各种修复细胞因子（如bFGF、VEGF、TGF-β）来调节损伤部位的微环境。因此，它调节参与再内皮化的各种细胞的行为，包括粘附、迁移、增殖、表型和归巢 [ 92 , 93]。然而，无论处于哪个阶段，都涉及各种相关的细胞和因子，有利的细胞行为和因子分泌可以迅速重塑血管。大量研究证明，MNPs 独特的磁性可以调节细胞行为和因子分泌，从而促进血管重塑[ 94 ]。MNPs 通过以下方式调节细胞行为和因子分泌： (1) MNPs 通过刺激标记细胞；(2) MNPs 标记的细胞对磁场有反应；(3) MNPs与材料结合，影响贴壁细胞行为和因素；(4) MNPs通过影响相关通路间接影响靶细胞的行为和因子分泌。Lshii 等人。[ 95 ] 通过结合 Fe ₃ O组装磁性细胞片₄纳米颗粒与间充质干细胞 (MSCs)，然后将它们移植到裸鼠的后肢，以评估血管生成的潜力。结果表明，磁性细胞片组血管生成更多，血管内皮生长因子表达增加，细胞凋亡减少。佩雷亚等人。[ 96] 首先用MNPs标记人平滑肌细胞（SMCs）和人脐静脉内皮细胞（HUVECs），然后利用径向磁力驱动细胞有效到达管状支架的管腔表面，将细胞固定在基质表面，粘附牢固，有效促进了血管内皮化进程。为了克服血管修复手术对内皮细胞层造成的不可逆损伤，导致血管功能受损和再狭窄，Vosen 和他的团队 [ 94] 将纳米技术与基因和细胞疗法相结合，用于位点特异性再内皮化和血管功能的恢复。研究人员使用慢病毒载体和 MNP 的复合物在内皮细胞 (EC) 中过度表达血管保护基因内皮一氧化氮合酶 (eNOS)。负载 MNPs 和过表达 eNOS 的细胞具有磁性，即使在流动条件下，它们也可以通过磁场以径向对称的方式定位在血管壁上。结果表明，处理后的血管显示出增强的 eNOS 表达和活性。此外，在血管损伤小鼠模型中，用过表达 eNOS 的细胞替代 EC 可恢复内皮功能。更有趣的是，Mattix 等人。[ 97] 通过 Janus 方法将 MNPs 添加到细胞球中，然后通过外部磁场 (EMF) 产生的磁力操纵细胞球融合成直径为 5 mm 的血管组织结构。对于 MNP 与材料的结合，Filippi 等人。[ 98] 通过将 MNP 掺入含有来自人类脂肪组织基质血管部分 (SVF) 的细胞的基于 PEG 的水凝胶中，制备了新型磁性纳米复合水凝胶；研究了外部静磁场 (SMF) 对构建体的血管生成特性的刺激。结果显示内皮细胞、周细胞和血管周围基因被强烈激活，VEGF和CD31(+)的表达增加。在小鼠皮下移植后，磁驱动结构显示出更致密、更矿化和更快血管化的组织。顾等人。[ 99] 研究了氧化铁纳米颗粒通过影响干扰素调节因子 5 (IRF5) 信号通路来调节巨噬细胞表型向 M1 极化和下调 M2 相关精氨酸酶 1 (Arg-1)，其中铁基 MNP 具有抗癌和抗癌作用。抑制肿瘤血管生成，提供新的见解。然而，MNPs 对巨噬细胞的表型极化具有浓度依赖性影响。许多研究表明，低剂量的 MNPs 也可以促进 M2 极化，但相关途径机制研究很少[ 100 , 101 ]。上述基于 MNPs 调节细胞和因子分泌的有利行为可以有效地参与血管修复。

MNPs have unique advantages in the construction of drug delivery systems (magnetic drug delivery, MDD), such as inherent magnetic targeting, magnetocaloric drug release, and accessible surface modification, which can maximize drug delivery. By applying a permanent magnet near the target tissue, the accumulation of MNPs at the target site can be induced, reducing the drug’s distribution in the whole body, thereby improving the therapeutic effect and reducing the toxic and side effects [104]. When using MNPs as drug delivery systems, the magnetic properties of nanoparticles are size-dependent, and magnetic nanoparticles with excellent performance can be obtained by adjusting the size. The charge and hydrophobic properties of MNPs affect their interactions with plasma proteins, the immune system, extracellular matrix, or non-targeted cells and determine their biological distribution. Hydrophobic MNPs readily adsorb plasma proteins, leading to recognition by the reticuloendothelial system and eventual clearance from the circulatory system under opsonization, resulting in a short circulating half-life. After modifying its surface with hydrophilic PEG and other molecules, its circulating half-life can be increased. Positively charged MNPs easily bind to non-targeted cells and undergo a nonspecific internalization process. Compared with negatively charged MNPs, positively charged MNPs generally exhibit higher cellular internalization effects [105,106]. In recent years, MDD systems have been widely developed to treat various diseases [107,108], including tumors, such as designing Fe₃O₄ nanoparticles-based targeted drug delivery systems to enhance cancer targeting to suppress tumors under static magnetic fields and laser irradiation growth, and the system proved effective for in situ transdermal drug delivery, magnetic fields, and synchronization of laser and biological targeting. Demonstrated in breast cancer models, this system is an effective alternative for the treatment of superficial cancers [109]; bone, for example, has developed an exosome derived from neutrophils modified by sub-5 nm ultra-small PBNP (uPB) engineering through click chemistry, which can target deep into cartilage, significantly improve the joint injury of CIA mice, and inhibit the overall severity of arthritis, showing considerable potential in the clinical diagnosis and treatment of arthritis [110]; in vascular structures, a developed nanoparticle (MMB-PLGA-PTX) can be used for in-stent restenosis (ISR) treatment that is responsive to external magnetic fields and LIFU. The results showed that magnetic targeting increased the accumulation of MMP-PLGA-PTX 10-fold, while LIFU facilitated the penetration of the released PLGA-PTX into the arterial tissue, thereby increasing the retention time of the released PTX in the stented vascular tissue. Combined with efficacy, this strategy holds great promise for the precise delivery of antiproliferative drugs to stented vascular tissue for ISR therapy [111]; skin, such as heme-modified prussian blue nanoparticles (PBNP, an iron-based magnetic nanoparticle) forms a colloid with NO, which is locally dropped at the skin wound site in response to NIR light and releases NO in a targeted and controllable manner to enhance blood Microcirculation, thereby effectively enhancing angiogenesis and collagen deposition during skin wound healing [112] . In the treatment of vascular injury, the main focus is on treating the etiology [113]. For example, arterial occlusion caused by external force injury or cardiovascular disease can cause severe mortality [114,115], so the rapid recanalization strategy can effectively reduce the risk of death. Intravenous injection of tissue plasminogen activator (tPA) at a fixed dose is the main method to dredge arterial occlusion [116,117]. Still, it will produce complications such as insufficient curative effect and bleeding. Therefore, magnetic drug targeting (MDT) is an effective therapeutic method, which uses an EMF to enhance the specific accumulation of drugs bound to MNPs in the diseased vascular system [118]. Ma et al. [119] first studied the possibility of local thrombolysis with MDT. MNPs combined with tPA (tPA equivalent is 0.2 mg/kg) were used in the rat embolism model. In this study, MNPs administered intravascularly moved and accumulated along the iliac artery affected by thrombus under the action of an external magnet, which resulted in effective targeted thrombolysis and was only less than 20% of the free tPA dose. Atherosclerosis (AS) is also a severe disease that can cause vascular damage [120,121]. Although many drugs can treat atherosclerosis [122,123,124], their systemic administration has serious disadvantages. In particular, the proportion of therapeutic dose reaching atherosclerotic lesions is small, resulting in poor therapeutic effect. Increasing the dose is often impossible in many cases because it can cause serious side effects and drug tolerance. Since the existing treatment strategies for AS are far from ideal, there is an urgent need for targeted therapy as an alternative strategy to exert better therapeutic effects. Cicha et al. [125] developed the combination of dexamethasone on MNPs, which magnetically targeted the balloon injury area in rabbits as well as advanced atherosclerotic plaques. Although the desired effect was not achieved, this may also be due to the selection of candidate drugs. In addition, myocardial infarction caused by coronary plaque rupture can also cause severe inflammation and even heart failure [126,127,128]. Zhang et al. [129] studied in a rat myocardial infarction model, using an in vitro epicardial magnet to accumulate MNPs that bind to the human VEGF gene encoded by an adenovirus vector in the ischemic area. Results showed that targeting MNPs resulted in higher VEGF gene expression in the affected area and better cardiac repair. Currently, the treatment of myocardial infarction with stem cell preparations promises to improve myocardial tissue recovery, but this is still limited due to poor accumulation and retention of therapeutic agents at target sites. Cheng et al. [130] used MNPs to enhance the targeted delivery of cardiac-derived stem cells (CDCs) in female rats with myocardial infarction. Then, a 1.3 T circular magnet was placed about 1 cm above the apex of the heart for 10 min, starting with an intramuscular injection of CDCs. During this process, the naked eye can see slight discoloration of adjacent tissues, suggesting that magnetic particle-labeled CDCs could prevent coronary washout. After 24 h, histology confirmed the retention of magnetic particle-labeled CDCs. Semi-quantitative fluorescence imaging showed that cells spread more in a subgroup of rats injected with non-magnetic or magnetically labeled CDCs without magnets than in rats that received labeled cells and additional magnetically targeted therapy to their lungs and spleen. Subsequently, the SRY gene that was decisively differentiated was analyzed by polymerase chain reaction (PCR). The results showed that CDCs implantation was three times higher in the myocardial tissue of rats in the magnetic target group. Therefore, the authors concluded that magnetic targeting could effectively attenuate the flushing of magnetic-particle-labeled CDCs at the injection site and significantly increase short-term CDCs engraftment in just 10 min. As targeted carriers, MNPs can effectively participate in the treatment of vascular injury. More applications can also be used as magnetic resonance contrast agents for MRI, which can accurately evaluate vascular functional and structural parameters to diagnose and treat.

Magnetic Resonance Imaging (MRI) is one of the most effective diagnostic imaging tools in medicine, providing clinicians with a high spatial and temporal resolution of biological anatomy and metabolic/functional information in a non-invasive manner. Tissue necrosis, ischemia, and other malignant diseases are of great significance. Under the action of an EMF, different tissues and organs of the organism can generate different resonance signals to form MR images. The strength of the resonance signal is determined by the water content of each part of the body and the relaxation time of water protons. The contrast agent is an image-enhancing contrast agent that can change the body’s relaxation rate of water protons, improve imaging contrast, and display lesions [29,32,131]. MNPs are considered to have promising applications in T2 MRI contrast agents, and especially iron-based MNPs exhibit longer half-lives than clinically used gadolinium-based contrast agents [132] (Figure 6). At present, a variety of iron-based MNPs have been developed as clinical MRI contrast agents for imaging various tissues. For example, the FDA approved Feridex to detect liver lesions, and Combidex has entered the phase III clinical trial stage for the imaging of lymph node metastasis [133]. In terms of vascular structures, in addition to participating in vascular repair in the above ways, MNPs can also be used as vascular microenvironment imaging contrast agents to observe the dynamic changes of vascular graft contour, stenosis or occlusion, and other abnormalities through image visualization to evaluate the process and effect of repair [134]. Flores et al. [135] demonstrated the feasibility of MRI to assess the in vivo performance of tissue-engineered vascular grafts (TEVG) by labeling human aortic smooth muscle cells (HASMCs) with USPIO nanoparticles, which were then seeded into a TEVG and implanted in mice in vivo. The results showed that USPIO-labeled TEVG consistently had sharper boundaries and lowered T2 relaxation time values than unlabeled control scaffolds. In addition, MNPs labeled cells were also used to observe the behavior of related vascular cells by MRI. Perea et al. [136] Labeled HUVECs with clinically approved SPIO, then drove cells to the lumen of polytetrafluoroethylene (PTFE) tubular grafts through a particular electromagnet and then detected endothelial cells with a 1.5 T magnetic resonance scanner to evaluate vascular endothelialization.

MNPs are exposed to alternating EMF, which triggers particle movement and local heating, which produces a high-temperature effect that causes tissue damage in the area around the nanoparticles and have been applied to tumor treatment. The main mechanism of action is to raise the temperature above 42 °C through magnetic heating and lead to protein denaturation, which leads to cell death. At present, this method has also been an effective means to treat tumor vascular injury. Higher thermal stimulation based on physiological temperature can effectively kill intravascular tumor cells [137,138] and inhibit blood flow to promote the recovery of vascular function [139]. In recent years, studies have also found that MNPs also have biological effects, such as promoting the polarization of macrophages and producing ROS effects. These effects will also have a significant impact on the vascular repair. Zanganeh et al. [140] found that high concentrations of ferumoxytol can promote macrophage polarization to M1, thereby enhancing the regulation of cancer immunotherapy, including breast cancer, liver cancer, and lung cancer. However, some scholars pointed out that a low concentration of MNPs can also promote the growth of blood vessels [101]. There is no more evidence to prove whether it may regulate the polarization of macrophages at the injured site to M2 type to promote repair.

MNPs participate in vascular injury repair based on their unique physicochemical properties. However, no matter how it participates in vascular repair, MNPs will pass through the blood circulatory system, affecting the vascular wall’s function, blood pressure, or hemodynamics. The most typical is that when INOPs are less than 7 nm, they will leak out of the vascular structures and be discharged by the kidney, while 200 nm–4 μM particles are easily phagocytized by macrophages of the mononuclear phagocytosis system (MPS). Therefore, the development of INOPs for vascular usually needs to be at 10–200 nm [158,159]. Secondly, it was known that the endothelial cell layer is the innermost layer of the vascular wall, which can maintain the hemostasis and smooth blood flow of vascular structures by releasing NO, heparin, plasmin, and other regulatory molecules [160,161]. The instability of INOPs sometimes leads to the release of iron ions, resulting in the dysfunction of most organelles in endothelial cells, such as lysosome, golgi apparatus, endoplasmic reticulum, and mitochondria, which in turn induces oxidative stress, inflammation, and gene mutation, and finally leads to the destruction of the endothelial cell layer, the impairment of vascular wall function, and thrombosis [162]。此外，通常裸露的 INOPs 容易在复杂的盐溶液（如血液）中聚集，对活组织或血管结构产生不利影响。稳定的抗聚集涂层，如血清白蛋白，可以大大提高 IONP 的分散性 [ 163 , 164 , 165 ]。更重要的是，研究表明离子浓度也会显着影响血压和血流动力学。