Jiazhen Niu, Meihui Su, De-E Liu, Na Li, Youtao Xin, Qixian Chen, Yunjian Yu, Feihe Ma, Mahmoud Elsabahy, Hui Gao
State Key Laboratory of Separation Membranes and Membrane Processes & Key Laboratory of Hollow Fiber Membrane Materials and Membrane Processes (MOE) & Tianjin Key Laboratory of Hollow Fiber Membrane Materials and Processes, School of Materials Science and Engineering, Tiangong University, Tianjin, 300387, P. R. China.
School of Materials Science and Engineering, Tianjin ChengJian University, Tianjin, 300384, P. R. China.
Adv Healthc Mater. 2024 Dec 19:e2402887. doi: 10.1002/adhm.202402887.
Fusobacterium nucleatum (Fn), as an intestinal pathogenic bacterium, is closely related to the occurrence, progression, and limited therapeutic efficacy of colorectal cancer (CRC). The presence of Fn within CRC communities induces an inflammatory and immunosuppressive microenvironment while promoting new vessel formation. Therefore, developing novel methods to efficiently eliminate Fn and enhance the therapeutic outcomes against Fn-associated CRC is of great significance. Herein, a nanosystem named AFGTs-PEG, which integrates antimicrobial agent lauric acid (LA), an antiangiogenic gene (sFlt-1), a targeted polymer (OEI-LA/PBA, OLP), and DSPE-mPEG, to boost the gene therapy of Fn-infected CRC, is developed. The sFlt-1 gene is delivered to CRC cells through lysosome escape, remarkably inhibiting new vessel formation at the CRC site and ultimately leading to CRC cell death. In principle, LA is used to eliminate Fn and its biofilms, and remodel the inflammatory and immunosuppressive microenvironment by restraining the generation of inflammatory factors and preventing polarization of M1 into M2 macrophages, thereby mitigating the adverse effects of Fn on antiangiogenic gene therapy. This study holds great promise for the treatment of bacteria-colonized tumors.
具核梭杆菌（Fn）作为一种肠道病原菌，与结直肠癌（CRC）的发生、发展及有限的治疗效果密切相关。CRC群落中Fn的存在会诱导炎症和免疫抑制微环境，同时促进新血管形成。因此，开发有效消除Fn并提高针对与Fn相关的CRC治疗效果的新方法具有重要意义。在此，开发了一种名为AFGTs-PEG的纳米系统，其整合了抗菌剂月桂酸（LA）、抗血管生成基因（sFlt-1）、靶向聚合物（OEI-LA/PBA，OLP）和DSPE-mPEG，以促进对Fn感染的CRC的基因治疗。sFlt-1基因通过溶酶体逃逸传递到CRC细胞中，显著抑制CRC部位的新血管形成并最终导致CRC细胞死亡。原则上，LA用于消除Fn及其生物膜，并通过抑制炎症因子的产生和防止M1巨噬细胞向M2巨噬细胞极化来重塑炎症和免疫抑制微环境，从而减轻Fn对抗血管生成基因治疗的不利影响。这项研究对细菌定植肿瘤的治疗具有很大的前景。
