In situ reprogramming of fibroblasts into antigen-presenting pseudo-dendritic cells via IFN-β-engineered protoplast-derived exosomes delivered by microneedle arrays to enhance adaptive immunity.

IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Theranostics Pub Date : 2025-08-16 eCollection Date: 2025-01-01 DOI:10.7150/thno.115080
Yue Yin, Shijie Zhao, Wei Li, Yuan Cui, Thanh Loc Nguyen, Ge Gao
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引用次数: 0

Abstract

Rationale: Dendritic cells (DCs) play a crucial role in adaptive immune responses; however, ex vivo differentiation strategies face operational complexities and reduced cellular viability. In situ reprogramming of resident cells into antigen-presenting cells represents a promising alternative approach for enhancing local immune responses. Methods: We initially introduce the novel concept of pseudo-DCs, in situ transforming intradermal fibroblasts into DC-like cells using an engineered exosome-loaded microneedle (MN) array. Specifically, engineered nano-protoplasts expressing interferon-beta (IFN-β) and loaded with varicella-zoster virus glycoprotein E (VZV gE) were used to stimulate DCs and derive immunostimulatory exosomes. These exosomes were integrated into a microarray-based delivery system for intradermal application. Results: The engineered exosomes (IdE@E) induced resident fibroblasts to upregulate DC surface co-stimulatory markers (CD80/86) and effectively present the model antigen. Transcriptome analysis also revealed significant upregulation of genes associated with immune response and antigen presentation in IdE@E-treated cells. In vivo studies demonstrated that MN array-delivered IdE@E effectively induced the expression of DC and activation markers from fibroblasts in dermis. Furthermore, MN array-delivered IdE@E significantly elevated the population of IFN-γ+CD8+ T cells in both lymph nodes and spleen, indicating enhanced local and systemic immune responses. Conclusions: This novel in situ reprogramming method represents a paradigm shift in precision immunotherapies, leveraging exosome-mediated cellular mimicry to enhance adaptive immunity without complete cellular transformation. This scalable framework holds significant promise for immunotherapy and could revolutionize personalized immunotherapy.

通过微针阵列递送IFN-β工程原生质体衍生外泌体,将成纤维细胞原位重编程为抗原呈递的伪树突状细胞,以增强适应性免疫。
理由:树突状细胞(dc)在适应性免疫反应中起着至关重要的作用;然而,体外分化策略面临操作复杂性和细胞活力降低的问题。将驻留细胞原位重编程为抗原呈递细胞是增强局部免疫反应的一种有希望的替代方法。方法:我们首先介绍了伪dc的新概念,利用工程外泌体负载微针(MN)阵列将皮内成纤维细胞原位转化为dc样细胞。具体来说,利用表达干扰素-β (IFN-β)并装载水痘-带状疱疹病毒糖蛋白E (VZV gE)的工程纳米原生质体刺激树突状细胞并获得免疫刺激外泌体。这些外泌体被整合到一个基于微阵列的皮内给药系统中。结果:工程外泌体(IdE@E)诱导驻留成纤维细胞上调DC表面共刺激标记(CD80/86)并有效呈递模型抗原。转录组分析还显示IdE@E-treated细胞中与免疫反应和抗原呈递相关的基因显著上调。体内研究表明,MN阵列递送IdE@E可有效诱导真皮成纤维细胞DC和激活标记物的表达。此外,MN阵列递送IdE@E显著提高了淋巴结和脾脏中IFN-γ+CD8+ T细胞的数量,表明局部和全身免疫反应增强。结论:这种新颖的原位重编程方法代表了精确免疫治疗的范式转变,利用外泌体介导的细胞模仿来增强适应性免疫,而不需要完全的细胞转化。这种可扩展的框架为免疫治疗带来了巨大的希望,并可能彻底改变个性化免疫治疗。
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来源期刊
Theranostics
Theranostics MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
25.40
自引率
1.60%
发文量
433
审稿时长
1 months
期刊介绍: Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.
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