开发工程菌用于解决缺氧肿瘤的瓶颈问题是活跃的研究领域，这些肿瘤通常对化疗、放疗和光动力疗法具有抵抗能力。在这里，我们报告了一种新方法，即利用纳米天线敏化的近红外工程菌（NASEB）以高效和双重选择的方式消除缺氧肿瘤。该方法采用了经过涂覆稀土上转换纳米颗粒（UCNPs）的工程大肠杆菌MG1655（EB）作为菌体表面的外部天线（MG1655/HlyE-sfGFP@UCNP@PEG），实现了NIR激光可开关的HlyE穿孔素的产生/分泌，从而杀死癌细胞。我们证明了通过其固有的趋化性在缺氧肿瘤部位富集NASEB，结合局部的NIR激光照射，可以抑制肿瘤并提高治疗的疗效和选择性，从而最小化癌症治疗中可能出现的副作用。与以往的报道不同，通过纳米天线敏化的工程菌进行的NIR响应开关具有独特性质，为针对缺氧肿瘤的治疗带来了概念上的新发展。研究的意义声明：肿瘤缺氧加剧了肿瘤的进展，同时也降低了传统化疗、放疗或光动力疗法的疗效。在这里，我们开发了近红外纳米天线敏化的工程菌（NASEB）来治疗缺氧肿瘤。NASEB能够通过其固有的趋化性在缺氧肿瘤部位积累和繁殖。接收到NIR激光信号后，NASEB表面的上转换纳米颗粒作为天线将其转换为蓝光，以激活EB蛋白质工厂中的HlyE穿孔素。我们的方法具有对肿瘤部位的双重选择性特点，既来源于厌氧菌的缺氧肿瘤趋向性，也来源于通过选择性NIR激光照射的空间限制。NASEB的概念有望解决肿瘤缺氧对癌症治疗的挑战。版权所有 © 2023 Elsevier Ltd. 发布。

It is an active research area in the development of engineered bacteria to address the bottleneck issue of hypoxic tumors, which otherwisely possess resistance to chemotherapies, radiotherapies, and photodynamic therapies. Here we report a new method to ablate hypoxic tumors with NIR-nanoantenna sensitized engineered bacteria (NASEB) in a highly effective and dual selective manner. It features engineered E. coli MG1655 (EB) with coatings of lanthanide upconversion nanoparticles (UCNPs) as external antennas on bacterial surface (MG1655/HlyE-sfGFP@UCNP@PEG), enabling NIR laser-switchable generation/secretion of HlyE perforin to kill cancer cells. We have demonstrated that NASEB enrichment on hypoxic tumor sites via their innate chemotactic tendency, in assistance of localized NIR laser irradiation, can suppress tumors with improved efficacy and selectivity, thus minimizing potential side effects in cancer treatment. The NIR-responsive nanoantenna sensitized switching in engineering bacteria is distinct from the previous reports, promising conceptually new development of therapeutics against hypoxic tumors. STATEMENT OF SIGNIFICANCE: Tumor hypoxia exacerbates tumor progression, but also reduces the efficacy of conventional chemotherapies, radiotherapies, or photodynamic therapies. Here we develop near infrared Nano Antenna Sensitized Engineered Bacteria (NASEB) to treat hypoxic tumors. NASEB can accumulate and proliferate on hypoxic tumor sites via their innate chemotactic tendency. After receiving NIR laser signals, the upconversion nanoparticles on NASEB surface as antennas can transduce them to blue light for activation of HlyE perforin in the protein factory of EB. Our method features dual selectivity on the tumor sites, contributed by hypoxic tumor homing of anaerobic bacteria and spatial confinement through selective NIR laser irradiation. The concept of NASEB promises to address the challenges of tumor hypoxia for cancer therapies.Copyright © 2023. Published by Elsevier Ltd.