武汉大学张先正研究小组的一项最新研究研究出L-半胱氨酸依赖细菌纳米药物生物杂化物靶向治疗肿瘤。相关论文于2025年4月10日发表在《细胞—代谢》杂志上。

研究组通过双选择定向进化策略精心开发了一种用于代谢治疗的L-半胱氨酸依赖型细菌-纳米药物生物杂合体。与野生型菌株相比，他们进化出的菌株-半胱氨酸摄取增加了36倍，半胱氨酸脱硫酶总活性提高了23倍。通过与负载DMXAA的脂质体偶联，该工程化生物杂合体不仅通过阻断新生血管阻止营养物质流入肿瘤，而且还实现了高效持久的胱氨酸（CySS）分解代谢。半胱氨酸类物质的缺失破坏了氧化还原稳态，显著增加了细胞内ROS水平，在多种肿瘤模型中获得了良好的治疗效果。他们的研究不仅突出了定向进化策略在提高细菌活性生物催化剂的稳定性和效率方面的前景，而且为抗肿瘤代谢治疗提供了新的机会。

据悉，以细菌为基础的代谢疗法已被认为是一种很有前途的肿瘤治疗策略。然而，野生型细菌的效率不足严重制约了其治疗效果。

附：英文原文

Title: Targeted tumor therapy with L-cyst(e)ine-addicted bacteria-nanodrug biohybrids

Author: Yu-Zhang Wang, Wei-Hai Chen, Zi-Yi Han, Shi-Man Zhang, Ping Ji, Cheng Zhang, Jun-Long Liang, Xian-Zheng Zhang

Issue&Volume: 2025-04-10

Abstract: Bacteria-based metabolic therapy has been acknowledged as a promising strategy for tumor treatment. However, the insufficient efficiency of wild-type bacteria severely restricts their therapeutic efficacy. Here, we elaborately develop an -cyst(e)ine-addicted bacteria-nanodrug biohybrid for metabolic therapy through a dual-selection directed evolution strategy. Our evolved strain exhibits a 36-fold increase in -cystine uptake and a 23-fold improvement in total activity of cysteine desulfhydrases compared with the wild-type strain. By conjugating with DMXAA-loaded liposomes, the engineered bacteria-nanodrug biohybrid not only prevents the influx of nutrients into the tumor by blocking neovasculature but also achieves efficient and durable CySS catabolism locally. The unavailable of Cys species disrupts redox homeostasis and strikingly increases intracellular ROS level, achieving favorable therapeutic outcomes in multiple tumor models. Our study not only highlights the promise of directed evolution strategy in enhancing the stability and efficiency of bacteria-based living biocatalyst but also provides new opportunities for antitumor metabolic therapy.

DOI: 10.1016/j.cmet.2025.03.012

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(25)00115-9