Fluolab【JACS】复旦大学李晓民等|突破合成瓶颈：280纳米病毒样稀土纳米颗粒实现特应性皮炎高效治疗
文章标题： Versatile Synthesis of Rare-Earth Nanoparticles with Virus-like Surface Nanotopography
通讯作者： Yan Yu, Wenxing Wang, Xiaomin Li
文章概要
纳米材料的表面形貌在调节纳米-生物界面相互作用中起着至关重要的作用。受自然界中病毒和花粉颗粒的启发，具有粗糙或刺突表面的纳米结构往往比平滑颗粒表现出更强的细胞摄取和生物功能。然而，由于稀土元素本身极快的水解动力学，如何精确控制具有复杂成分的稀土纳米颗粒的表面拓扑结构一直是一个巨大的合成挑战。复旦大学赵东元院士团队及李晓民教授等研究者通过一种创新的π–π共轭驱动的胶束反转策略，成功合成了一系列具有病毒样表面形貌的稀土氧化物纳米颗粒，并将其应用于特应性皮炎的治疗，展示了形貌工程在提升生物医药疗效方面的巨大潜力。
Figure 1. Synthesis and characterization of rare-earth oxide with virus-like surface nanotopography. (a) Schematic illustration of the synthesis of virus-like mesoporous rare-earth nanoparticles in an oil–water biphase system. (b) FESEM and (c) TEM images of the obtained v-mCe(OH)x with virus-like surface nanotopography. (d) 2D cross section and (e) representative views of TEM tilt series of v-mCe(OH)x. (f) Schematic illustration of the transformation of a rare-earth nanoparticle from hydroxide to oxide. (g) XRD patterns and (h) XPS spectra of Ce 3d of v-mCe(OH)x and v-mCeO2. (i, k) HRTEM, (j) EDS elemental mapping images, and (l) corresponding SAED patterns of v-mCeO2. Scale bar: (j) 50 nm.
引言
在纳米医学领域，通过调节颗粒的大小、形状或组成来优化功能已是常态，但表面拓扑工程作为一种新兴策略，为调节细胞摄取、免疫激活和组织渗透提供了独特的维度。稀土纳米颗粒凭借其独特的4f电子构型，在多模态成像、催化和抗氧化治疗中具有无可比拟的优势。然而，传统的合成方法往往只能得到粒径分布宽、形貌简单的产物。稀土前驱体在水解过程中的快速沉淀与表面活性剂胶束的缓慢自组装动力学之间存在严重的不匹配。为了克服这一障碍，本研究提出利用特殊的表面活性剂相互作用来控制组装路径，旨在开发一个通用的合成平台，以构建具有病毒样刺突结构的多功能稀土纳米材料。
Figure 2. The generality of the strategy for the synthesis of virus-like rare-earth hydroxides (v-mRE(OH)x) and oxides (v-mREOx). (a) Scheme illustration and (b) TEM images of single-component v-mRE(OH)x. (c) Scheme illustration, (d) TEM, and (e) EDS elemental mapping images of manganese-doped virus-like nanoparticles (v-mMn/Ce(OH)x). (f) Scheme illustration, (g, i) TEM and (h, j) EDS elemental mapping images of multicomponent v-mRE(OH)x. (k) XRD patterns of multicomponent and transition metal-doped v-mREO_x_. Scale bar: (b, d, g, i) 100 nm; (e, h, j) 50 nm.
主要实验及结论
研究人员开发了一种基于π–π共轭驱动的油水两相合成体系，利用十六烷基甲基咪唑氯化铵（C16MImCl）作为结构导向剂，并通过水杨酸钠（NaSal）的π–π堆积作用调节胶束结构。实验发现，当NaSal与表面活性剂的比例达到1:1时，体系会发生从油包水到水包油的胶束反转，促使稀土低聚物在亲水结构域内各向异性生长，最终形成了粒径约280纳米、表面带有约35纳米长刺突的病毒样颗粒。该策略具有极高的通用性，不仅适用于铈、镨、钕、钆等多种单一稀土元素，还能制备从二元到七元的高熵稀土氧化物，甚至可以进行过渡金属掺杂而不破坏其独特的刺突形貌。
Figure 3. Mechanism of π–π conjugation-driven micelle inversion strategy. (a) Intermolecular interactions between the imidazolium groups of the C16MImCl surfactant and the salicylate anions of the NaSal cosurfactant. CLSM images of water–oil biphasic system at NaSal/C16MImCl ratio of (b) 1:2 and (c) 5:4. Red fluorescence for Nile Red-stained oil phase; green fluorescence for FITC-stained aqueous phase. (d) Schematic illustration of the molecular arrangement at the water–oil interface and the intermolecular π–π interactions used for MD simulation. The dihedral angle θ is defined as the angle between the plane of the imidazole ring and the water–oil interface. (e) Temporal evolution of θ in C16MImCl/NaSal systems with 1:1 and 2:1 molar ratios, recorded over 80 ns of MD simulation. Radial distribution functions (RDFs) of (f) the benzene ring of NaSal and (g) the imidazole ring of C16MImCl around a reference imidazole ring of C16MImCl. (h) Micelle structures in the water–oil biphasic system, showing the transition from oil-in-water micelles (I) to water-in-oil micelles (II) with increasing NaSal cosurfactant. The nanoparticles in the SEM images are presented with pseudocolor overlays. Scale bars for SEM images: 100 nm.
Figure 4. In vitro ROS scavenging and cellular uptake of v-mCeO2 for atopic dermatitis treatment. (a) Schematic illustration of v-mCeO2 as a therapeutic agent for atopic dermatitis treatment. (b) Oxygen-evolving curves catalyzed by v-mCeO2 with virus-like surface nanotopography or CeO2 with smooth surface in the presence of 100 mM of H2O2. (c) ESR spectra of •O2– generated by the photocatalytic H2O2 Fenton system in the presence of v-mCeO2 or CeO2. (d) ESR spectra of •OH generated by the Fe2+ + H2O2 Fenton system in the presence of v-mCeO2 or CeO2. (e) Total antioxidant capacity of varying concentrations of v-mCeO2 and CeO2 measured by ABTS assay. (f) CLSM images, (g) flow cytometry analysis, and (h) fluorescence intensity quantification of HaCaT cells after coincubation with FITC-labeled v-mCeO2 or CeO2. (i) CLSM images and (j) flow cytometry analysis of DCFH-DA-stained HaCaT cells following different treatments. All data are presented as mean ± s.d. The concentration of nanoparticles: (b, c, d, f, g) 200 μg/mL; (i, j) 50 μg/mL.
在功能验证环节，研究团队重点考察了病毒样介孔二氧化铈（v-mCeO2）的抗氧化性能。实验结果显示，由于刺突结构提供了更大的比表面积和更多的活性位点，v-mCeO2的模拟酶催化效率显著优于平滑表面颗粒。更为关键的是，这种病毒样形貌通过物理互锁机制增强了颗粒与皮肤组分的粘附力。在细胞实验中，v-mCeO2的细胞摄取量是平滑颗粒的2.6倍，展示了极强的活性氧（ROS）清除能力。在针对小鼠特应性皮炎（AD）模型的活体实验中，v-mCeO2能够深入渗透至真皮层并富集于皮肤附件，有效缓解了皮肤增厚和炎症细胞浸润，其治疗效果明显优于临床常用对照组及平滑颗粒组。
Figure 5. In vivo therapeutic efficacy of v-mCeO2 for the atopic dermatitis mouse model. (a) Schematic illustration of DNCB-induced AD-like mouse model and therapeutic regimen. (b) CLSM images and (c) corresponding fluorescence intensity quantification of mouse skin sections after topical application of FITC-labeled v-mCeO2 or conventional CeO2. SC, stratum corneum; EP, epidermis; and DM, dermis. The green-fluorescent-enriched skin appendages such as glands are marked by red triangles in CLSM images. (d) Representative photographs of mouse skin after dermatitis induction and different treatments. (e) Dermatitis scores of the four groups during the whole treatment period. (f) Representative H&E-stained histological sections of mouse skin. The black-boxed regions are magnified below, with the distance between the red lines indicating the epidermal thickness. (g) Quantification of epidermal thickness in each group. (h) Representative toluidine blue-stained histological sections of mouse skin showing dermal mast cells (marked with red triangles). (i) Quantification of mast cell numbers in each group. (j) Representative immunofluorescence images of 8-OHdG. (k) Fluorescence intensity quantification of 8-OHdG in each group. (l, m) Quantitative analysis of the positive area of TNF-α, TSLP, IL-4, and IL-13 in each group. Scale bars for all histology sections and fluorescence images: 100 μm. All data are shown as mean ± s.d. NS, no statistical significance. ****P < 0.0001, ***P < 0.001, **P < 0.01, *P < 0.05 by two-way ANOVA (c), and one-way ANOVA (g, i, k, l, m).
总结及展望
这项研究成功建立了一个通用的稀土纳米材料拓扑调控平台，通过分子间相互作用的精细调控解决了稀土组装动力学失衡的问题。病毒样形貌的引入不仅显著提升了材料的生物界面交互能力和催化活性，也为临床治疗氧化应激相关疾病提供了新的思路。未来，这种基于拓扑结构优化性能的策略有望扩展到更多领域，如高性能催化剂的设计和多模态生物成像探针的开发。通过深入探索纳米材料几何形状与生物学效应之间的深层逻辑，研究者们将能够更精准地设计出符合临床需求的智能化多功能纳米药物。