基于 DNA 超分子水凝胶的保护性 NK 细胞储库用于增强三阴性乳腺癌治疗
Protective NK Cell Reservoir Based on DNA Supramolecular Hydrogel for Enhanced Triple-Negative Breast Cancer Therapy.
过继性自然杀伤（NK）细胞疗法是治疗三阴性乳腺癌的一种有前景的策略，但其疗效往往受到瘤内持久性差以及在免疫抑制性肿瘤微环境中功能耗竭的限制。
98.9分
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CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
利用人 iPSC-小胶质细胞实现疾病修饰蛋白的中枢神经系统全范围递送
英文原题：Harnessing human iPSC-microglia for CNS-wide delivery of disease-modifying proteins.
研究概要
将治疗性蛋白广泛递送至大脑仍然具有挑战性。
中文摘要
将治疗性蛋白广泛递送至大脑仍然具有挑战性。为确定人诱导多能干细胞（iPSC）来源的小胶质细胞（iMG）是否能够实现全脑范围且对病理状态有响应的治疗性载荷递送，我们利用 CRISPR 基因编辑技术对 iMG 进行工程化改造，使其在斑块响应型启动子 CD9 的控制下表达 Aβ 降解酶脑啡肽酶。为进一步确定提高植入率是否会增强疗效，我们采用了 CSF1R 抑制剂耐药策略。有趣的是，在阿尔茨海默病（AD）小鼠中，局部植入和全脑植入均降低了多项病理学的生化指标。然而，在斑块密集的海马下托中，只有在广泛的小胶质细胞植入后才能实现斑块负荷、营养不良性神经突和星形胶质细胞增生的减少以及神经元密度的保留。最后，我们检查了乳腺癌脑转移和脱髓鞘的嵌合模型，证明 iMG 对不同神经病理学表现出多样的转录反应，这可用于实现对 CNS 的广泛且病理响应性治疗递送。
展开英文摘要原文
Widespread delivery of therapeutic proteins to the brain remains challenging. To determine whether human induced pluripotent stem cell (iPSC)-microglia (iMG) could enable brain-wide and pathology-responsive delivery of therapeutic cargo, we utilized CRISPR gene editing to engineer iMG to express the Aβ-degrading enzyme neprilysin under control of the plaque-responsive promoter, CD9. To further determine whether increased engraftment enhances efficacy, we utilized a CSF1R-inhibitor resistance approach. Interestingly, both localized and brain-wide engraftment in Alzheimer's disease (AD) mice reduced multiple biochemical measures of pathology. However, within the plaque-dense subiculum, reductions in plaque load, dystrophic neurites, and astrogliosis and preservation of neuronal density were only achieved following widespread microglial engraftment. Lastly, we examined chimeric models of breast cancer brain metastases and demyelination, demonstrating that iMG adopt diverse transcriptional responses to differing neuropathologies, which could be harnessed to enable widespread and pathology-responsive delivery of therapeutics to the CNS.
论文信息
- 作者
- Chadarevian JP、Davtyan H、Chadarevian AL、Nguyen J、Capocchi JK、Le L、Escobar A、Chadarevian T
- 第一作者单位
- Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA 92697, USA; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92697, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA.United States
- 通讯作者单位
- Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA 92697, USA; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92697, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA. Electronic address: mblurton@uci.edu.United States
- 文献类型
- 非美国政府资助研究 · 美国 NIH 资助研究 · 美国政府（非公共卫生署）资助研究
- 期刊
- Cell stem cell2025 Jun 5
- 原文标识
- PubMed 40233761 · DOI 10.1016/j.stem.2025.03.009