Targeting capacity, safety and efficacy of engineered extracellular vesicles delivered by transdermal microneedles to treat plasmacytoma in mice

IF 7.9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine Pub Date : 2025-05-02 DOI:10.1002/ctm2.70327

Yulin Cao, Xuan Hu, Di Wu, Yuxuan Jiang, Yali Yu, Shan Wang, Wenlan Chen, Yaoying Long, Liuyue Xu, Jiao Qu, Bianlei Yang, Blal Chakhabi, Hongxiang Wang, Yong Deng, Lei Chen, Zhichao Chen, Qiubai Li

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引用次数: 0

Abstract

Background

Engineered extracellular vesicles (EVs) are emerging as a highly potential platform for targeted drug delivery in cancer therapy. Although intravenous injection is commonly used in EV treatment, there is growing interest in using microneedles (MNs) for transdermal EV delivery; however, comprehensive studies comparing the tissue distribution, safety and antitumour efficacy of these two approaches for delivering engineered EVs remain scarce.

Methods

We used EVs derived from umbilical cord mesenchymal stem cells, modified with phospholipid‒polyethylene glycol‒N-hydroxysuccinimide and conjugated with CD38 peptides (CD38-EVs), to target myeloma cells that highly express CD38 antigen, and tested their safety and antitumour efficacy in mice with subcutaneous plasmacytoma, administrated via dissolvable transdermal MNs or intravenous injection. Flow cytometry, immunofluorescence and fluorescence molecular projection imaging analysis were employed to evaluate the distribution of CD38-EVs at the cellular level and within living systems. Additionally, histopathological analysis and biochemical analyses were conducted to assess the antitumour effects and safety of CD38-EVs loaded with doxorubicin (CD38-EVs-Dox).

Results

Compared to standard EVs, CD38-EVs exhibited enhanced uptake by CD38^high tumour cells and reduced uptake by CD38-negative non-tumour cells in vitro. In plasmacytoma NOD/SCID mouse models, CD38-EVs encapsulated within MNs (CD38-EVs^MNs) effectively targeted the tumour cells much more than the standard EVs encapsulated within MNs (EVs^MNs) and CD38-EVs intravenously administrated (CD38-EVs^i.v), with reduced distribution to the lungs and spleen. Additionally, CD38-EVs-Dox induced significantly greater cytotoxicity against the tumour cells than EVs-Dox in vitro, and CD38-EVs-Dox^MNs significantly reduced tumour burden compared to both EVs-Dox^MNs and CD38-EVs-Dox^i.v, while maintaining favourable safety profiles.

Conclusions

CD38-EVs-Dox^MNs have superior efficacy and safety in treating plasmacytoma mice, compared to CD38-EVs-Dox^i.v, providing novel insights into the potential of MNs as a platform for delivering targeted engineered EVs in tumour therapy.

Highlights

Enhanced tumor targeting: CD38-modified EVs (CD38-EVs) showed increased uptake by CD38high tumor cells while reducing uptake by CD38-negative non-tumor cells.
Optimized delivery: MN-loaded CD38-EVs targeted tumors more effectively than MN-loaded EVs and intravenously injected CD38-EVs, with lower lung and spleen accumulation.
Superior antitumor efficacy: MN-delivered CD38-EVs-Dox significantly suppressed tumor growth, outperforming intravenous CD38-EVs-Dox and MN-delivered EVs-Dox.

Abstract Image

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经皮微针输送的工程细胞外囊泡治疗小鼠浆细胞瘤的靶向能力、安全性和有效性

背景工程细胞外囊泡（EVs）正在成为癌症治疗中极具潜力的靶向药物递送平台。虽然静脉注射通常用于EV治疗，但使用微针（MNs）经皮给药EV的兴趣越来越大；然而，比较这两种方法的组织分布、安全性和抗肿瘤功效的综合研究仍然很少。方法：采用磷脂-聚乙二醇- n -羟基丁二酰亚胺修饰的脐带间充质干细胞衍生的ev，结合CD38肽（CD38- ev）靶向高度表达CD38抗原的骨髓瘤细胞，并通过可溶透皮MNs或静脉注射给药，检测其在皮下浆细胞瘤小鼠中的安全性和抗肿瘤效果。采用流式细胞术、免疫荧光和荧光分子投影成像分析方法评价cd38 - ev在细胞水平和生命系统内的分布。此外，通过组织病理学分析和生化分析来评估负载阿霉素（cd38 - ev - dox）的cd38 - ev的抗肿瘤作用和安全性。结果与标准ev相比，cd38 - ev对cd38高表达的肿瘤细胞的摄取增强，对cd38阴性的非肿瘤细胞的摄取减少。在浆细胞瘤NOD/SCID小鼠模型中，包裹在MNs内的cd38 - ev （CD38-EVsMNs）比包裹在MNs内的标准ev （EVsMNs）和静脉给药的cd38 - ev （CD38-EVsi.v）更有效地靶向肿瘤细胞，并且减少了肺和脾脏的分布。此外，cd38 - ev - dox在体外诱导的肿瘤细胞毒性显著高于ev - dox， cd38 - ev - doxns与ev - doxns和cd38 - ev - doxi相比，显著降低了肿瘤负担。V，同时保持良好的安全概况。结论cd38 - ev - doxns治疗小鼠浆细胞瘤的疗效和安全性优于cd38 - ev - doxi。v，为MNs作为肿瘤治疗中靶向工程化ev平台的潜力提供了新的见解。增强的肿瘤靶向性：cd38修饰的ev （cd38 - ev）显示cd38高的肿瘤细胞摄取增加，而cd38阴性的非肿瘤细胞摄取减少。优化递送：mn负载的cd38 - ev比mn负载的ev和静脉注射的cd38 - ev更有效地靶向肿瘤，肺和脾脏积聚更低。优越的抗肿瘤效果：mn给药cd38 - ev - dox显著抑制肿瘤生长，优于静脉注射cd38 - ev - dox和mn给药ev - dox。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.