通过工程噬菌体在哺乳动物肠道中持续的原位蛋白质生产和释放，这一成果由美国弗吉尼亚理工大学Bryan B. Hsu团队经过不懈努力而取得。2025年2月18日出版的《自然—生物技术》发表了这项成果。

在这里，该团队展示了噬菌体（噬菌体）的工程，感染常驻共生体，表达在细胞裂解过程中释放的异源蛋白。研究人员利用以常驻非致病性大肠杆菌为目标的强毒T4噬菌体，首先鉴定出蛋白表达最高、对T4噬菌体滴度影响最小的T4特异性启动子。该课题组研究人员设计了T4噬菌体来表达一种促炎酶的丝氨酸蛋白酶抑制剂，在溃疡性结肠炎中活性增加，并在结肠炎模型中观察到酶活性降低。该课题组还将该方法应用于饮食性肥胖的无主题模型中，以减少体重增加和炎症。这项工作强调了在哺乳动物肠道中应用毒性噬菌体作为可工程载体，从常驻肠道细菌中释放治疗药物。

据了解，由于上胃肠道的降解活性，口服生物药物具有挑战性。主题工程微生物在下胃肠道生产生物制剂的策略受到与常驻共生细菌竞争的限制。

附：英文原文

Title: Sustained in situ protein production and release in the mammalian gut by an engineered bacteriophage

Author: Baker, Zachary R., Zhang, Yao, Zhang, Haiyan, Franklin, Hollyn C., Serpa, Priscila B. S., Southard, Teresa, Li, Liwu, Hsu, Bryan B.

Issue&Volume: 2025-02-18

Abstract: Oral administration of biologic drugs is challenging because of the degradative activity of the upper gastrointestinal tract. Strategies that use engineered microbes to produce biologics in the lower gastrointestinal tract are limited by competition with resident commensal bacteria. Here we demonstrate the engineering of bacteriophage (phage) that infect resident commensals to express heterologous proteins released during cell lysis. Working with the virulent T4 phage, which targets resident, nonpathogenic Escherichia coli, we first identify T4-specific promoters with maximal protein expression and minimal impact on T4 phage titers. We engineer T4 phage to express a serine protease inhibitor of a pro-inflammatory enzyme with increased activity in ulcerative colitis and observe reduced enzyme activity in a mouse model of colitis. We also apply the approach to reduce weight gain and inflammation in mouse models of diet-induced obesity. This work highlights an application of virulent phages in the mammalian gut as engineerable vectors to release therapeutics from resident gut bacteria.

DOI: 10.1038/s41587-025-02570-7

Source: https://www.nature.com/articles/s41587-025-02570-7