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Reactive Oxygen Species-Triggered Carbon Dots-Based Biomimetic Nanotheranostic Agents for Atherosclerosis Management
活性氧触发的碳纳米点仿生治疗动脉粥样硬化药物

Xinmei Duan, Xu Yang, Nianlian Mou, Yu Cao, Zhigui He, Li Zhu, Yuan Zhong, Kun Zhang, Kai Qu, Xian Qin, Qiao Chen,* Yang Luo,* and Wei Wu*
Xinmei Duan，Xu Yang，Nianlian Mou，Yu Cao，Zhigui He，Li Zhu，Yuan Zhong，Kun Zhang，Kai Qu，Xian Qin，Qiao Chen，* Yang Luo，* and Wei Wu*

Abstract 摘要

Atherosclerosis (AS) is a chronic inflammation vascular disease, with its ongoing progression can lead to the onset of cardiovascular diseases. Traditional drug therapy is limited by poor drug delivery, insufficient drug accumulation, and notable toxic side effects. In addition, the failure to receive an early AS diagnosis is primarily responsible for the delayed treatment, which subsequently contributes to the high frequency of life-threatening cardiovascular events. In this work, a macrophage membranes (MM)-camouflaged reactive oxygen species (ROS)-sensitive nanotheranostic platform (LC-MM) is constructed to improve AS target diagnosis and treatment efficacy. Thanks to the strong antioxidant properties of carbon dots (CDs), CDs as drug carriers for lovastatin aimed to synergistically treat AS by reducing ROS accumulation and suppressing inflammatory responses in vitro and in vivo are employed. The active functions of MM coupled with the ROS-responsiveness of LC nanoplatform are expected to enhance the efficacy of nanotherapy, particularly to reduce lipid deposition, macrophage infiltration, necrotic core size, collagen content, pro-inflammatory cytokines, and oxidative stress accumulation. Moreover, the near-infrared emission properties inherited from CDs facilitated precise fluorescence (FL) imaging for AS plaques. Thus, the biomimetic nanotheranostic agent LC-MM represented a powerful platform for safe and effective AS management.
动脉粥样硬化（AS）是一种慢性炎症性血管疾病，其不断发展可导致心血管疾病的发生。传统的药物治疗受到药物传递差、药物蓄积不足和明显毒副作用的限制。此外，未能接受早期AS诊断是延迟治疗的主要原因，随后导致危及生命的心血管事件的高频率。在这项工作中，构建了巨噬细胞膜（MM）-包裹活性氧（ROS）-敏感的纳米治疗诊断平台（LC-MM），以提高AS的靶向诊断和治疗效果。由于碳量子点（CD）的强抗氧化特性，CD作为洛伐他汀的药物载体，旨在通过减少ROS积累和抑制体外和体内炎症反应来协同治疗AS。 MM的活性功能与LC纳米平台的ROS响应性相结合，预计将增强纳米治疗的功效，特别是减少脂质沉积、巨噬细胞浸润、坏死核心大小、胶原蛋白含量、促炎细胞因子和氧化应激积累。此外，从CD继承的近红外发射特性促进了AS斑块的精确荧光（FL）成像。因此，仿生纳米治疗剂LC-MM代表了安全有效的AS管理的强大平台。

1. Introduction 1.介绍

Atherosclerosis (AS) is considered a chronic inflammatory disease induced by endothelial dysfunction, which is mainly
动脉粥样硬化（AS）被认为是一种由内皮功能障碍引起的慢性炎症性疾病，其主要
characterized by the deposition of lipids (cholesterol and lipoproteins, etc.) and plaque formation within the arterial wall. [ 1 − 3 ] [ 1 − 3 ] ^([1-3]){ }^{[1-3]} The narrowing of the vascular lumen and acute rupture of plaques caused by the thickening and hardening of the vessel wall is one of the major causes of fatal cardiovascular events. [ 4 ] [ 4 ] ^([4]){ }^{[4]} Currently, the accessible therapeutic options for pharmacological intervention and treatment of AS in the clinic including antihypertension, [ 5 ] [ 5 ] ^([5]){ }^{[5]} antihyperlipidemia, [ 6 ] [ 6 ] ^([6]){ }^{[6]} and anticoagulation to reduce thrombosis, [ 7 ] [ 7 ] ^([7]){ }^{[7]} exhibited limited therapeutic efficacy, with the underlying reason being lack of target and effective drug delivery. In order to improve drug bioavailability and reduce toxic side effects associated with non-specific distribution, various nanomaterials, including polymers, [ 8 − 10 ] [ 8 − 10 ] ^([8-10]){ }^{[8-10]} liposomes, [ 11 , 12 ] [ 11 , 12 ] ^([11,12]){ }^{[11,12]} and micelles, [ 13 , 14 ] [ 13 , 14 ] ^([13,14]){ }^{[13,14]} have been widely exploited for targeted drug delivery systems. [ 15 ] [ 15 ] ^([15]){ }^{[15]} Furthermore, to improve the therapeutic effects of drugs for AS management, the combined approach of diagnosis and treatment has emerged as a new trend in nanomaterial design to create nanotheranostic agents. On the one hand, fluorescence (FL) imaging has been demonstrated to be capable of identifying the microstructures of biological entities, and offers numerous advantages compared to the traditional imaging techniques, thanks to its
以脂质（胆固醇和脂蛋白等）沉积为特征。和动脉壁内的斑块形成。 [ 1 − 3 ] [ 1 − 3 ] ^([1-3]){ }^{[1-3]} 血管壁增厚和硬化导致的血管腔狭窄和斑块急性破裂是致命性心血管事件的主要原因之一。 [ 4 ] [ 4 ] ^([4]){ }^{[4]} 目前，临床上可获得的药物干预和治疗AS的治疗选择包括降压、 [ 5 ] [ 5 ] ^([5]){ }^{[5]} 降脂、 [ 6 ] [ 6 ] ^([6]){ }^{[6]} 和抗凝以减少血栓形成， [ 7 ] [ 7 ] ^([7]){ }^{[7]} 显示出有限的治疗效果，其根本原因是缺乏靶向和有效的药物递送。为了提高药物的生物利用度和减少与非特异性分布相关的毒副作用，各种纳米材料，包括聚合物， [ 8 − 10 ] [ 8 − 10 ] ^([8-10]){ }^{[8-10]} 脂质体， [ 11 , 12 ] [ 11 , 12 ] ^([11,12]){ }^{[11,12]} 和胶束， [ 13 , 14 ] [ 13 , 14 ] ^([13,14]){ }^{[13,14]} 已被广泛开发用于靶向药物递送系统。 此外，为了提高AS管理药物的治疗效果，诊断和治疗的组合方法已成为纳米材料设计的新趋势，以创建纳米治疗诊断剂。 一方面，荧光（FL）成像已被证明能够识别生物实体的微观结构，并且与传统成像技术相比具有许多优势，这要归功于其
non-invasiveness, high sensitivity, and modifiable functionality. [ 16 , 17 ] [ 16 , 17 ] ^([16,17]){ }^{[16,17]} Mostly, the organic fluorescent probes are selected as contrast agents covalently bonded to nanomaterials for the preparation of nanotheranostic agents. [ 18 , 19 ] [ 18 , 19 ] ^([18,19]){ }^{[18,19]} On the other hand, the application of the organic fluorescent probes is limited to the complex synthesis processes, light instability, and inherent toxicity. For instance, the prolonged use of semiconductor quantum dots as diagnostic agents might give toxic side effects from the resulting metal ions. [ 20 , 21 ] [ 20 , 21 ] ^([20,21]){ }^{[20,21]} Therefore, designing fluorescent probes that are easy to synthesize and highly biocompatible, along with drug carriers that can be easily modified, is important for the advancement of ideal nanotheranostic agents.
非侵入性、高灵敏度和可修改的功能。 [ 16 , 17 ] [ 16 , 17 ] ^([16,17]){ }^{[16,17]} 大多数情况下，选择有机荧光探针作为与纳米材料共价键合的造影剂，用于制备纳米治疗诊断剂。 [ 18 , 19 ] [ 18 , 19 ] ^([18,19]){ }^{[18,19]} 另一方面，有机荧光探针的应用受限于复杂的合成过程、光不稳定性和固有毒性。例如，长期使用半导体量子点作为诊断剂可能会产生金属离子的毒副作用。 [ 20 , 21 ] [ 20 , 21 ] ^([20,21]){ }^{[20,21]} 因此，设计易于合成和高度生物相容的荧光探针，以及易于修饰的药物载体，对于理想的纳米治疗诊断剂的发展至关重要。
In recent years, fluorescent carbon-based nanomaterials (carbon dots (CDs)) have received considerable attention. When comparing CDs with organic fluorescent probes or semiconductor quantum dots, CDs offer several benefits, including simple preparation, tunable emission, excellent photostability, and favorable biocompatibility. [ 22 ] [ 22 ] ^([22]){ }^{[22]} Some specifically designed CDs also have additional activities, including antioxidant, [ 23 ] [ 23 ] ^([23]){ }^{[23]} antibacterial, [ 24 ] [ 24 ] ^([24]){ }^{[24]} and antiviral. [ 25 ] [ 25 ] ^([25]){ }^{[25]} Given these exceptional properties, CDs can be used to construct nanotheranostic agents, contributing to their potential applications for bioimaging, disease monitoring, and therapy. [ 26 − 29 ] [ 26 − 29 ] ^([26-29]){ }^{[26-29]} Furthermore, CDs have demonstrated superior water dispersity and the abundant functional groups on the surface can improve their versatile functionalization and further applications. [ 27 , 30 ] [ 27 , 30 ] ^([27,30]){ }^{[27,30]} Therefore, CDs were selected to construct the nanotheranostic agents for AS management.
近年来，基于荧光碳的纳米材料（碳量子点（CD））受到了相当大的关注。当将CD与有机荧光探针或半导体量子点进行比较时，CD提供了几个优点，包括制备简单、可调谐发射、优异的光稳定性和良好的生物相容性。 [ 22 ] [ 22 ] ^([22]){ }^{[22]} 一些特别设计的CD还具有额外的活性，包括抗氧化剂， [ 23 ] [ 23 ] ^([23]){ }^{[23]} 抗菌， [ 24 ] [ 24 ] ^([24]){ }^{[24]} 和抗病毒。 [ 25 ] [ 25 ] ^([25]){ }^{[25]} 鉴于这些特殊的性质，CD可用于构建纳米治疗诊断剂，有助于其在生物成像、疾病监测和治疗方面的潜在应用。 [ 26 − 29 ] [ 26 − 29 ] ^([26-29]){ }^{[26-29]} 此外，CD还表现出优异的上级水分散性，表面丰富的官能团可以提高其多功能化和进一步的应用。 [ 27 , 30 ] [ 27 , 30 ] ^([27,30]){ }^{[27,30]} 因此，选择CD来构建用于AS管理的纳米治疗剂。
The application of non-specific targeted nanoagents might induce adverse effects in normal tissues and organs upon in vivo administration. The direct coupling of targeted ligands to nanoagents is a common approach to functionalize nanoagents for better disease targeting, [ 23 , 31 ] [ 23 , 31 ] ^([23,31]){ }^{[23,31]} but it might have some limitations, such as specialized molecular design, complex synthesis, and difficult purification. The biomimetic drug delivery systems, especially cell membrane-cloaked nanoagents have attracted tremendous attention due to their unrivaled biological structure and functionality derived from the source cell. [ 32 − 34 ] [ 32 − 34 ] ^([32-34]){ }^{[32-34]} Macrophage, a critical component of plaques, is commonly recruited by chemokines to accumulate at inflammatory lesions. It is a promising strategy to exploit the natural inflammatory chemotaxis of macrophage for the local target drug delivery into plaque. In addition, optimizing the design of nanoagents to modulate drug release in the plaque is another key factor for safe and efficient AS treatment. [ 35 , 36 ] [ 35 , 36 ] ^([35,36]){ }^{[35,36]} The excessive reactive oxygen species (ROS) accumulation in AS pathology can be exploited as an endogenous stimulus to trigger the local drug release for the precise AS treatment. [ 37 − 40 ] [ 37 − 40 ] ^([37-40]){ }^{[37-40]}
非特异性靶向纳米制剂的应用可能在体内给药后在正常组织和器官中引起不良反应。靶向配体与纳米药物的直接偶联是使纳米药物功能化以更好地靶向疾病的常用方法， [ 23 , 31 ] [ 23 , 31 ] ^([23,31]){ }^{[23,31]} 但它可能具有一些局限性，例如专门的分子设计，复杂的合成和难以纯化。仿生给药系统，特别是细胞膜包裹的纳米制剂，由于其无与伦比的生物结构和功能来源于源细胞而引起了人们的极大关注。 [ 32 − 34 ] [ 32 − 34 ] ^([32-34]){ }^{[32-34]} 巨噬细胞是斑块的关键成分，通常被趋化因子招募以在炎性病变处积聚。利用巨噬细胞的趋炎性作用将药物局部靶向输送到斑块内是一种很有前途的策略。 此外，优化纳米制剂的设计以调节斑块中的药物释放是安全有效治疗AS的另一个关键因素。 [ 35 , 36 ] [ 35 , 36 ] ^([35,36]){ }^{[35,36]} AS病理中过量的活性氧（ROS）积累可作为内源性刺激来触发局部药物释放，用于精确的AS治疗。 [ 37 − 40 ] [ 37 − 40 ] ^([37-40]){ }^{[37-40]}
Herein, a biomimetic ROS-sensitive nanotheranostic agent (LC-MM) was constructed for targeted imaging and treatment in AS. CDs derived from reduced glutathione have been reported to have deep red emission and strong antioxidant properties, [ 29 ] [ 29 ] ^([29]){ }^{[29]} which can be useful in developing the nanotheranostic agents. In addition, lovastatin (LVT), a classical cholesterol-lowering drug, was chosen as the drug candidate aiming to inhibit the proinflammatory cytokines. In this design, LVT was grafted on the surface of CDs via oxalyl chloride (OC) to accelerate a rapid cargo release triggered by the pathological ROS. [ 41 − 43 ] [ 41 − 43 ] ^([41-43]){ }^{[41-43]} Benefiting from the key functional membrane proteins of macrophage membrane (MM), integrin α 4 β 1 α 4 β 1 alpha4beta1\alpha 4 \beta 1, which efficiently recognizes and in-
本文构建了一种仿生ROS敏感纳米治疗诊断剂（LC-MM），用于AS的靶向成像和治疗。已报道衍生自还原型谷胱甘肽的CD具有深红色发射和强抗氧化性质， [ 29 ] [ 29 ] ^([29]){ }^{[29]} 可用于开发纳米治疗诊断剂。此外，经典的降胆固醇药物洛伐他汀（LVT）被选为旨在抑制促炎细胞因子的候选药物。在该设计中，LVT通过草酰氯（OC）接枝在CD表面上以加速由病理性ROS触发的快速货物释放。 [ 41 − 43 ] [ 41 − 43 ] ^([41-43]){ }^{[41-43]} 受益于巨噬细胞膜（MM）的关键功能膜蛋白，整合素 α 4 β 1 α 4 β 1 alpha4beta1\alpha 4 \beta 1 ，其有效地识别和整合-
teracts with the over-expressed vascular cell adhesion protein 1 (VCAM-1) on the membrane surface of inflammatory endothelial cells, [ 44 − 48 ] [ 44 − 48 ] ^([44-48]){ }^{[44-48]} the biomimetic nanotheranostic agents were expected to enhance the target accumulation in AS plaques for the efficient diagnosis and therapy. Thus, LC-MM represents a highly promising and optimal multi-functional integrated nanoplatform for safe and efficient AS management (Scheme 1).
与炎性内皮细胞膜表面过表达的血管细胞粘附蛋白1（VCAM-1）相互作用， [ 44 − 48 ] [ 44 − 48 ] ^([44-48]){ }^{[44-48]} 仿生纳米治疗剂有望增强AS斑块中的靶向积聚，从而实现有效的诊断和治疗。因此，LC-MM代表了一种非常有前途和最佳的多功能集成纳米平台，用于安全和有效的AS管理（方案1）。

2. Results and Discussion
2.结果和讨论

2.1. Preparation and Characterization of LC-MM
2.1. LC-MM的制备和表征

In this study, LC-MM was prepared following procedure as shown in Figure 1A. LC was synthesized by esterification and amidation reactions of OC with LVT and CDs, respectively. As previously reported, CDs were synthesized by the solvothermal method using the reduced glutathione as a precursor and formamide as a solvent. [ 49 ] [ 49 ] ^([49]){ }^{[49]} Transmission electron microscopy (TEM) images showed that CDs were in uniform quasi-spherical morphology with an average diameter of 2.03 nm and favorable dispersion (Figure 1B). High-resolution (HR) TEM image showed the clear lattice stripes, which were consistent with the (100) facets of graphite, suggesting that CDs contained a graphite-like structure. A current report showed that multifunctional CDs prepared by the reduced glutathione as a precursor have abundant amino groups on the surface, offering the promising possibility for functional modification as drug carriers. [ 49 ] [ 49 ] ^([49]){ }^{[49]} In order to construct ROS-sensitive nanoparticles, LVT was covalently conjugated into CDs using OC to form LC that can self-assemble into nanostructures in aqueous solution with a quasi-spherical shape with an average diameter of about 31 nm (Figure 1B), as observed under HR-TEM. In addition, the corresponding HR-TEM images showed that lattice streaks of 0.21 nm belonging to multifunctional CDs were uniformly distributed on the surface of LC. The hydrogen nuclear magnetic resonance ( 1 H 1 H (^(1)H:}\left({ }^{1} \mathrm{H}\right. NMR) spectra of LC showed the new proton signals belonging to amide groups, with resonance peaks at 6.6-7.3 ppm, demonstrating that the CDs and LVT were covalently conjugated via OC (Figure 1C). The above results confirmed that LC had been successfully synthesized by a simple method with a drug loading efficiency (LE) of 48.4 % w / w 48.4 % w / w 48.4%w//w48.4 \% \mathrm{w} / \mathrm{w} and a drug grafting efficiency (GE) of 54.7% w/w (Figures S1 and S2, Supporting Information).
在本研究中，按照图1A所示的程序制备LC-MM。LC是由OC分别与LVT和CD进行酯化和酰胺化反应合成的。如前所述，使用还原型谷胱甘肽作为前体，甲酰胺作为溶剂，通过溶剂热法合成CD。 [ 49 ] [ 49 ] ^([49]){ }^{[49]} 透射电子显微镜（TEM）图像显示CD呈均匀的准球形形态，平均直径为2.03 nm，分散性良好（图1B）。高分辨透射电子显微镜（HR TEM）图像显示出清晰的晶格条纹，与石墨的（100）面一致，表明CD含有类石墨结构。以还原型谷胱甘肽为前体制备的多功能CD表面含有丰富的氨基，为药物载体的功能化修饰提供了可能。 为了构建ROS敏感的纳米颗粒，使用OC将LVT共价缀合到CD中以形成LC，LC可以在水溶液中自组装成具有平均直径约31 nm的准球形形状的纳米结构（图1B），如在HR-TEM下观察到的。此外，相应的HR-TEM图像显示，液晶表面均匀分布着属于多功能CD的0.21 nm晶格条纹。LC的氢核磁共振（2#NMR）谱显示属于酰胺基团的新质子信号，在6.6- 7.3ppm处具有共振峰，表明CD和LVT经由OC共价缀合（图1C）。上述结果证实LC已通过简单方法成功合成，载药效率（LE）为 48.4 % w / w 48.4 % w / w 48.4%w//w48.4 \% \mathrm{w} / \mathrm{w} ，药物接枝效率（GE）为54.7%w/w（图S1和S2，支持信息）。
In order to endow LC with the biomimetic function of the active target delivery to AS plaques, MM was coated on the surface of LC by co-extrusion technique (Figure 1A). The morphology of LC-MM was observed by TEM images (Figure 1B). The results showed that LC-MM maintained a spherical surface morphology and the existence of a corona structure on the outer layer. The TEM images of LC-MM showed that the average particle size of LC-MM was about 35 nm , increasing by 4.5 nm compared to that of LC. This result was further verified by dynamic light scattering (DLS), which showed that the average hydrodynamic diameter of the nanoparticles increased from ≈ 74 nm ≈ 74 nm ~~74nm\approx 74 \mathrm{~nm} to ≈ 89 nm ≈ 89 nm ~~89nm\approx 89 \mathrm{~nm} after the MM coating (Figure 1D). Meanwhile, the polydispersity index (PDI) of the nanoparticles was in the range of 0.1 − 0.2 0.1 − 0.2 0.1-0.20.1-0.2, indicating that the nanoparticles were well dispersed and uniformly distributed. In addition, the zeta potential of LC-MM with the negatively charged MM coating was near to the zeta potential of MM, predicting the successful coating of the MM on the LC surface
为了使LC具有向AS斑块递送活性靶标的仿生功能，通过共挤出技术将MM涂覆在LC表面（图1A）。通过TEM图像观察LC-MM的形态（图1B）。结果表明，LC-MM保持了球形表面形貌，外层存在电晕结构。LC-MM的TEM图像显示LC-MM的平均粒径约为35 nm，与LC相比增加了4.5 nm。该结果通过动态光散射（DLS）进一步验证，其显示在MM涂覆后纳米颗粒的平均流体动力学直径从 ≈ 74 nm ≈ 74 nm ~~74nm\approx 74 \mathrm{~nm} 增加到 ≈ 89 nm ≈ 89 nm ~~89nm\approx 89 \mathrm{~nm} （图1D）。同时，纳米颗粒的多分散指数（PDI）在 0.1 − 0.2 0.1 − 0.2 0.1-0.20.1-0.2 范围内，表明纳米颗粒分散良好且均匀分布。 此外，具有带负电荷的MM涂层的LC-MM的zeta电位接近MM的zeta电位，预测MM在LC表面上的成功涂覆
Scheme 1. Scheme of LC-MM preparation and its application for AS management.
方案一. LC-MM制备方案及其在AS管理中的应用
(Figure 1E). Moreover, the characteristic P elements of MM were uniformly distributed on the surface of LC-MM (Figure 1F), supporting the successful preparation of the MM-coated nanoparticles. To further verify the successful coating of MM, the colocalization of MM and LC was observed by fluorescent labeling. As shown in Figure S3 (Supporting Information), MM and LC had a strong co-localization. These results confirmed that the coextrusion technique could effectively harvest the biomimetic nanotheranostic agents. Except for the coated cell membrane structure, LC-MM was expected to inherit the biological functions mediated by the membrane proteins of MM. The protein profiles
（图1 E）。此外，MM的特征性P元素均匀分布在LC-MM的表面上（图1F），支持MM涂覆的纳米颗粒的成功制备。为了进一步验证MM的成功包被，通过荧光标记观察MM和LC的共定位。如图S3（支持性信息）所示，MM和LC具有较强的共定位。这些结果证实了共挤出技术可以有效地收获仿生纳米治疗剂。除了细胞膜结构外，LC-MM还可能继承MM膜蛋白介导的生物学功能。
of MM, LC, and LC-MM demonstrated that LC-MM could retain the membrane proteins of MM completely (Figure S4, Supporting Information). In addition, protein immunoblotting assay further validated the successful retention of the key functional proteins in LC-MM, including integrin α 4 α 4 alpha4\alpha 4 and integrin β 1 β 1 beta1\beta 1, which are able to specifically recognize and bind to VCAM-1, and CC chemokine receptor 2 (CCR2), the receptor for monocyte chemotactic protein-1 (MCP-1) (Figure 1G). [ 46 , 50 ] [ 46 , 50 ] ^([46,50]){ }^{[46,50]} Overall, LC-MM could be successfully obtained by the co-extrusion technique, and LCMM well inherited the biological functions from the mother cells of macrophages.
对MM、LC和LC-MM的分析表明，LC-MM可完全保留MM的膜蛋白（图S4，支持性信息）。此外，蛋白质免疫印迹测定进一步验证了关键功能蛋白在LC-MM中的成功保留，包括整合素 α 4 α 4 alpha4\alpha 4 和整合素 β 1 β 1 beta1\beta 1 ，其能够特异性识别并结合VCAM-1和CC趋化因子受体2（CCR 2），单核细胞趋化蛋白-1（MCP-1）的受体（图1G）。 [ 46 , 50 ] [ 46 , 50 ] ^([46,50]){ }^{[46,50]} 总体而言，LC-MM可以通过共挤出技术成功获得，并且LCMM很好地继承了巨噬细胞母细胞的生物学功能。
  1. X. Duan, X. Yang, N. Mou, Y. Cao, Z. He, L. Zhu, Y. Zhong, K. Zhang, K. Qu, X. Qin, Q. Chen, W. Wu
    X. Duan，X. Yang，N.牟，Y.曹，Z.赫利湖，加-地Zhu，Y. Zhong，K. Zhang，K. Qu，X.秦，越-地陈威吴
    Key Laboratory for Biorheological Science and Technology of Ministry of Education
    生物流变科学与技术教育部重点实验室
    State and Local Joint Engineering Laboratory for Vascular Implants Bioengineering College of Chongqing University
    重庆大学生物工程学院血管植入物国家地方联合工程实验室
    Chongqing 400044, P. R. China
    邮编：400044中国
    E-mail: 20211901033@stu.cqu.edu.cn; david2015@cqu.edu.cn
    电子邮件地址：david2015@cqu.edu.cn 20211901033@stu.cqu.edu.cn
    K. Zhang, K. Qu, X. Qin
    K. Zhang，K. Qu，X.秦
    Chongqing University Three Gorges Hospital
    重庆大学三峡医院
    Chongqing 404000, P. R. China
    邮编：404000中国
    The ORCID identification number(s) for the author(s) of this article can be found under https://doi.org/10.1002/adfm . 202405629
    本文作者的ORCID识别号可在https://doi.org/10.1002/adfm下找到。202405629
    DOI: 10.1002/adfm . 202405629
    DOI：10.1002/adfm. 202405629
  2. Y. Luo Y.罗
    Department of Clinical Laboratory Medicine
    临床检验医学系
    Chongqing General Hospital
    重庆总医院
    School of Medicine 医学院
    Chongqing University 重庆大学
    Chongqing 400044, P. R. China
    邮编：400044中国
    E-mail: luoy@cqu.edu.cn  电子邮件地址：luoy@cqu.edu.cn
    Y. Luo Y.罗
    College of Life Science and Laboratory Medicine
    生命科学与实验医学学院
    Kunming Medical University
    昆明医科大学
    Kunming, Yunnan 650050, P. R. China
    中国云南昆明650050中国
    Y. Luo, W. Wu Y.罗，W.吴
    JinFeng Laboratory 金峰实验室
    Chongqing 401329, P. R. China
    邮编：401329中国