Engineered commensals for targeted nose-to-brain drug delivery

IF 45.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Pub Date : 2025-02-05 DOI:10.1016/j.cell.2025.01.017

Haosheng Shen, Nikhil Aggarwal, Beiming Cui, Guo Wei Foo, Yuanzhi He, Santosh Kumar Srivastava, Shengjie Li, Marcus Ze Xian Seah, Kwok Soon Wun, Hua Ling, In Young Hwang, Chun Loong Ho, Yung Seng Lee, Matthew Wook Chang

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Abstract

Intranasal administration through the olfactory epithelium (OE) presents a direct pathway for brain-targeted therapeutic delivery, although its feasibility is hampered by the anatomical and absorptive limitations of the OE. In this study, we identified Lactobacillus plantarum WCFS1 (Lp), a commensal strain with a natural affinity for the OE and engineered it to function as a vector for cerebral drug delivery. Upon intranasal administration, Lp released specific payload molecules within the OE, with subsequent transport and accumulation in the brain. The therapeutic efficacy of Lp was further validated by the recombinant production and secretion of appetite-regulating hormones. When administered intranasally in a murine model of obesity prevention, the engineered Lp significantly alleviated obesity-related symptoms. This was evidenced by decreased appetite, reduced body weight gain, and improved glucose metabolism and fat mass deposition. Our study demonstrates the capability of Lp as an intranasal delivery vehicle, emphasizing its potential for brain-targeted therapeutic applications.

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用于靶向鼻到脑药物输送的工程共生体

鼻内给药通过嗅上皮（OE）为脑靶向治疗提供了一条直接途径，尽管其可行性受到OE解剖和吸收限制的阻碍。在这项研究中，我们鉴定了一种与OE具有天然亲和力的共生菌株植物乳杆菌WCFS1 (Lp)，并将其改造为脑药物传递载体。经鼻给药后，Lp在OE内释放特定的有效载荷分子，随后在大脑中运输和积累。通过重组食欲调节激素的产生和分泌，进一步验证了Lp的治疗效果。在预防肥胖的小鼠模型中，经鼻给药后，工程Lp显著减轻了肥胖相关症状。这可以通过食欲下降、体重增加减少、葡萄糖代谢和脂肪堆积改善来证明。我们的研究证明了Lp作为鼻内给药载体的能力，强调了其在脑靶向治疗应用方面的潜力。

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来源期刊

Cell 生物-生化与分子生物学

CiteScore

110.00

自引率

0.80%

发文量

396

审稿时长

2 months

期刊介绍： Cells is an international, peer-reviewed, open access journal that focuses on cell biology, molecular biology, and biophysics. It is affiliated with several societies, including the Spanish Society for Biochemistry and Molecular Biology (SEBBM), Nordic Autophagy Society (NAS), Spanish Society of Hematology and Hemotherapy (SEHH), and Society for Regenerative Medicine (Russian Federation) (RPO). The journal publishes research findings of significant importance in various areas of experimental biology, such as cell biology, molecular biology, neuroscience, immunology, virology, microbiology, cancer, human genetics, systems biology, signaling, and disease mechanisms and therapeutics. The primary criterion for considering papers is whether the results contribute to significant conceptual advances or raise thought-provoking questions and hypotheses related to interesting and important biological inquiries. In addition to primary research articles presented in four formats, Cells also features review and opinion articles in its "leading edge" section, discussing recent research advancements and topics of interest to its wide readership.