预表观重编程超活性细胞外囊泡在重大疾病中的研究进展
1. 中科生物智造创新中心, 北京 100407
2. 中科健兰医学研究院, 北京 100407
3. 中国科学院生物物理研究所, 北京 100101
| 摘 要： | 人脐带间充质干细胞（human umbilical cord mesenchymal stem cell, hUC-MSC）来源小细胞外囊泡（small extracellular vesicles, sEVs）作为无细胞再生医学核心制剂，具备低免疫原性、多生物屏障穿透、多通路协同调控、给药安全性高等独特优势，为炎症、退行性、神经发育类难治性疾病提供全新干预策略。天然未修饰 sEVs 存在活性载物无定向富集、纯化杂质残留超标、多给药途径适配性不足、全链条质控体系缺失等临床转化瓶颈。中国科学院生物物理研究所联合中科生物智造创新中心、中科健兰医学研究院构建预表观重编程定向修饰 + 四级梯度 GMP 模块化纯化原创成套技术体系，通过调控 ESCRT 分选表观信号重塑囊泡蛋白、细胞因子、调控型非编码 RNA 载物谱，定向制备黏膜抗炎修复、全身免疫调控、软组织软骨修复三类功能亚型 sEVs；同步搭建适配雾化吸入、鼻黏膜递送、眼用、静脉输注、关节腔注射、局部病灶给药、皮下注射七类临床给药途径的 GLP 级标准化检定框架。本文系统阐述工程化超活性 sEVs 的制备原理、多维度理化表征与 CMC 全链条质控规范，围绕重症肺部损伤、孤独症谱系障碍、神经退行性病变、骨关节炎、全身性自身免疫病五大类重大难治性疾病解析分子干预机制，结合临床真实干预队列数据验证体内安全性与治疗增益；系统梳理当前工程化 sEVs 产业化与临床转化关键技术壁垒，提出靶向膜修饰、多中心大样本随机对照临床、全产业链标准化建设等迭代研发路径，为标准化细胞外囊泡生物治疗产品开发、临床前药理毒理评价及药品注册转化提供完整理论与实践支撑。 |
| 关 键 词： | 预表观重编程; 人脐带间充质干细胞; 小细胞外囊泡; 无细胞治疗; 重大难治性疾病; 再生医学; 标准化质量控制 |
| DOI： | 10.57237/j.mrf.2026.04.001 |
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收稿日期: 2026-08-23
接受日期: 2026-09-20
在线出版日期: 2026-10-08
Advances in Pre-Epigenetically Reprogrammed Hyperactive Extracellular Vesicles for Major Diseases
1. Zhongke Bio-Manufacturing Innovation Center, Beijing 100407, China
2. Zhongke Jianlan Medical Research Institute, Beijing 100407, China
3. Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| Abstract: | Human umbilical cord mesenchymal stem cell (hUC-MSC)-derived small extracellular vesicles (sEVs) serve as core cell-free regenerative therapeutics, featuring low immunogenicity, multi-barrier penetrability, multi-pathway synergistic regulation, and superior administration safety, which deliver innovative intervention strategies for refractory inflammatory, degenerative and neurodevelopmental disorders. Native unmodified sEVs are restricted by critical translational bottlenecks, including non-directional enrichment of bioactive cargos, excessive residual impurities post-isolation, poor compatibility across diverse administration routes, and the absence of full-chain quality control frameworks. An interdisciplinary research team co-established by the Institute of Biophysics, Chinese Academy of Sciences, Zhongke Bio-Manufacturing Innovation Center and Zhongke Jianlan Medical Research Institute developed an original integrated technical platform combining pre-epigenetic reprogramming directional modification and four-stage gradient GMP modular purification. By regulating epigenetic signals of the ESCRT sorting cascade, the system remodels the cargo spectrum of vesicular proteins, cytokines and regulatory non-coding RNAs, enabling directional production of three functional sEV subtypes: mucosal anti-inflammatory repair subtype, systemic immunomodulatory subtype, and soft tissue & cartilage regeneration subtype. Meanwhile, a GLP-standardized full-dimensional testing system matching seven clinical delivery routes (nebulized inhalation, intranasal delivery, ophthalmic administration, intravenous infusion, intra-articular injection, local lesion delivery, subcutaneous injection) was constructed. This review systematically elaborates the preparation principle, multi-dimensional physicochemical characterization and full-chain CMC quality specifications of engineered hyperactive sEVs, dissects molecular intervention mechanisms in five categories of severe refractory diseases including critical pulmonary injury, autism spectrum disorder, neurodegenerative diseases, osteoarthritis and systemic autoimmune disorders, and validates in vivo safety and therapeutic efficacy via real-world clinical cohort data. We comprehensively analyze current technical barriers restricting industrialization and clinical translation of engineered sEVs, and propose iterative research strategies including targeted membrane modification, multi-center large-sample randomized controlled clinical trials, and standardized full-industry-chain construction, providing systematic theoretical support and practical basis for standardized development of extracellular vesicle therapeutics, preclinical pharmacology & toxicology evaluation, and regulatory registration transformation. |
| Keywords: | Pre-epigenetic Reprogramming; Human Umbilical Cord Mesenchymal Stem Cells; Small Extracellular Vesicles; Cell-free Therapy; Major Refractory Diseases; Regenerative Medicine; Standardized Quality Control |
参考文献
| [1] | Welsh JA, et al. Minimal information for studies of extracellular vesicles 2023 (MISEV2023). Journal of Extracellular Vesicles, 2024, 13(1): e12433. |
| [2] | Chen J, et al. Human umbilical cord mesenchymal stromal cell small extracellular vesicle transfer of microRNA-223-3p attenuates inflammation in acute lung injury in mice. Journal of Nanobiotechnology, 2025, 23(1): 219. |
| [3] | Bertolino GM, Maumus M, Jorgensen C, et al. Therapeutic potential in rheumatic diseases of extracellular vesicles derived from mesenchymal stromal cells. Nature Reviews Rheumatology, 2023, 19(9): 547–564. |
| [4] | Zhang Y, et al. Extracellular vesicles for Alzheimer’s disease therapy: mechanisms, engineering strategies, and clinical translation. Advanced Science, 2026, 13(12): e2504128. |
| [5] | Liu Y, et al. Preconditioned mesenchymal stem cell-derived small extracellular vesicles: epigenetic cargo reprogramming and translational advances. Acta Biomaterialia, 2024, 172: 289–306. |
| [6] | Wang Z, et al. Engineered mesenchymal stem cell sEVs mitigate organ fibrosis via macrophage phenotype reprogramming. Biomaterials, 2026, 401: 122441. |
| [7] | Pham TT, et al. Nasal delivery of mesenchymal stem cell extracellular vesicles rescues neuroinflammation and autistic-like behaviors via TLR4/NF-κB inhibition. Brain, Behavior, and Immunity, 2025, 132: 418–432. |
| [8] | Zhang X, et al. Engineered MSC-sEVs for cartilage regeneration in osteoarthritis: multi-target matrix protection and synovial immunomodulation. Biomaterials Research, 2024, 28(1): 65. |
| [9] | Valadi H, et al. Cell-free therapeutics based on engineered small extracellular vesicles: industrial standardization and clinical regulatory challenges. Nature Reviews Drug Discovery, 2025, 24(3): 217–236. |
| [10] | Yan Z, et al. Epigenetic reprogramming amplifies therapeutic miRNA loading within mesenchymal stem cell small extracellular vesicles. Advanced Functional Materials, 2024, 34(28): e24018967. |
| [11] | Escudier B, et al. Extracellular vesicles as human therapeutics: systematic scoping review of clinical trial data. Journal of Extracellular Vesicles, 2024, 13(1): e12433. |
| [12] | Sun Y, et al. Mesenchymal stem cell-derived extracellular vesicles modulate Treg/Th17 balance to restore systemic immune tolerance in autoimmune disorders. Cellular & Molecular Immunology, 2025, 22(4): 678–694. |
| [13] | Valadi H, et al. Cell-free therapeutics based on engineered small extracellular vesicles: industrial standardization and clinical regulatory challenges. Nature Reviews Drug Discovery, 2025, 24(3): 217–236. |
| [14] | Ma Y, Dong S, Grippin A, et al. Engineering therapeutical extracellular vesicles for clinical translation. Trends in Biotechnology, 2025, 43(1): 61–82. |
| [15] | Louro AF, Meliciano A, Alves PM, et al. A roadmap towards manufacturing extracellular vesicles for cardiac repair. Trends in Biotechnology, 2024, 42(10): 1305–1322. |
