Precision-engineered bacterial nanovectors for synergetic co-delivery to harness cellular senescence and immunomodulation for enhanced tumor eradication

IF 13.3 1区工程技术 Q1 ENGINEERING, CHEMICAL

Chemical Engineering Journal Pub Date : 2025-01-12 DOI:10.1016/j.cej.2025.159533

Zixuan Ye, Yuanzhuo Zhou, Lizhen Liang, Jiahui Zhao, Wenzheng Liu, Lingtong Meng, He Huang, Jingpeng Yang, Xinping Lin, Yanan Li

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引用次数: 0

Abstract

The combination of chemotherapy and immunotherapy, for example, doxorubicin and anti-PD-L1 antibody, has been a crucially synergistic cancer treatment. However, the poor intratumoral distribution and limited immunogenicity still impede its antitumor efficacy. To overcome these problems, live bacterial cell factory was introduced as delivery carrier to improve the effect, and further clarify the boosting mechanism of live bacteria in clinical of combination therapy. Herein, we rigorously optimized an anti-PD-L1 nb-expressed E. coli Nissle1917(ECNp) to exert accurate secretion in the hypoxia tumor environment, and doxorubicin-loaded liposome (Dox-Lip) was coated on the surface of EcNp by acid-sensitive imine bond linker. In malignant melanoma models, based on the superior antitumor effect, we found this EcNp-based carrier significantly triggers tumor cell senescence, which increases antigen presentation and causes IFN-γ-dependent immune response, reinforcing the immunogenic death induced by doxorubicin and upregulating the expression of PTEN in tumor cells to increase the sensitivity to anti-PD-L1 nb, playing a “hub” role of cascade-amplified antitumor effect. Moreover, with reliable safety, this EcNp-based hybrid provides a universal platform for the combined penetrant delivery of proteins and small-molecule drugs in advanced cancers.

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精密工程细菌纳米载体协同共递送利用细胞衰老和免疫调节增强肿瘤根除

化疗和免疫治疗的结合，如阿霉素和抗pd - l1抗体，是一种至关重要的协同癌症治疗方法。但其肿瘤内分布差，免疫原性有限，仍制约其抗肿瘤效果。为了克服这些问题，引入活菌细胞工厂作为递送载体，提高效果，进一步明确活菌在临床联合治疗中的促进作用机制。本研究严格优化了一种抗pd - l1 nb表达的大肠杆菌Nissle1917(ECNp)，使其在缺氧肿瘤环境下精确分泌，并通过酸敏亚胺键连接剂包被负载阿霉素的脂质体（Dox-Lip）在ECNp表面。在恶性黑色素瘤模型中，基于其优越的抗肿瘤作用，我们发现该基于ecnp的载体显著触发肿瘤细胞衰老，增加抗原呈递，引起IFN-γ依赖性免疫应答，强化阿霉素诱导的免疫原性死亡，上调肿瘤细胞PTEN的表达，增加抗pd - l1 nb的敏感性，发挥级联扩增抗肿瘤作用的“枢纽”作用。此外，这种基于ecnp的混合物具有可靠的安全性，为晚期癌症中蛋白质和小分子药物的联合渗透递送提供了一个通用平台。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Chemical Engineering Journal 工程技术-工程：化工

CiteScore

21.70

自引率

9.30%

发文量

6781

审稿时长

2.4 months

期刊介绍： The Chemical Engineering Journal is an international research journal that invites contributions of original and novel fundamental research. It aims to provide an international platform for presenting original fundamental research, interpretative reviews, and discussions on new developments in chemical engineering. The journal welcomes papers that describe novel theory and its practical application, as well as those that demonstrate the transfer of techniques from other disciplines. It also welcomes reports on carefully conducted experimental work that is soundly interpreted. The main focus of the journal is on original and rigorous research results that have broad significance. The Catalysis section within the Chemical Engineering Journal focuses specifically on Experimental and Theoretical studies in the fields of heterogeneous catalysis, molecular catalysis, and biocatalysis. These studies have industrial impact on various sectors such as chemicals, energy, materials, foods, healthcare, and environmental protection.