Guo Lina, Chen Hao, Ding Jinsong, Rong Pengfei, Sun Ming, Zhou Wenhu
Xiangya School of Pharmaceutical Sciences Central South University Changsha China.
Department of Pathology Shihezi University School of Medicine Shihezi China.
Exploration (Beijing). 2023 Oct 5;3(6):20230017. doi: 10.1002/EXP.20230017. eCollection 2023 Dec.
Bacteria-based microbial immunotherapy shows various unique properties for tumor therapy owing to their active tropism to tumor and multiple anti-tumor mechanisms. However, its clinical benefit is far from satisfactory, which is limited by rapid systemic clearance and neutrophils-mediated immune restriction to compromise the efficacy, as well as non-specific distribution to cause toxicity. To address all these limitations, herein we reported a polyserotonin (PST) coated () with surface adsorption of DNAzyme (Dz)-functionalized MnO nanoparticles (DzMN) for tumor therapy. PST could facilely coat on surface via oxidation and self-polymerization of its serotonin monomer, which enabled surface stealth to avoid rapid systemic clearance while maintaining the tumor homing effect. Upon targeting to tumor, the PST was degraded and exfoliated in response to acidic tumor microenvironment, thus liberating to recover its anti-tumor activities. Meanwhile, the DzMN was also delivered into tumor via hitchhiking , which could release Dz and Mn after tumor cells internalization. The Dz was then activated by its cofactor of Mn to cleave target PD-L1 mRNA, thus serving as a self-activated system for gene silencing. Combining and Dz for immune activation and PD-L1 knockdown, respectively, anti-tumor immunotherapy was achieved with enhanced efficacy. Notably, PST coating could significantly decrease infection potential and non-specific colonization of at normal organs, achieving high in vivo biosafety. This work addresses the key limitations of for in vivo application via biomaterials modification, and provides a promising platform for better microbial immunotherapy.
基于细菌的微生物免疫疗法因其对肿瘤的主动趋向性和多种抗肿瘤机制，在肿瘤治疗中展现出各种独特特性。然而，其临床疗效远不能令人满意，受到快速的全身清除以及中性粒细胞介导的免疫限制而影响疗效，还存在非特异性分布导致毒性等问题。为解决所有这些局限性，在此我们报道了一种用聚血清素（PST）包被的（此处原文似乎有缺失内容），其表面吸附有DNA酶（Dz）功能化的MnO纳米颗粒（DzMN）用于肿瘤治疗。PST可通过其血清素单体的氧化和自聚合轻松地包被在（此处原文似乎有缺失内容）表面，实现表面隐身以避免快速的全身清除，同时保持肿瘤归巢效应。靶向肿瘤后，PST会响应酸性肿瘤微环境而降解并脱落，从而释放出（此处原文似乎有缺失内容）以恢复其抗肿瘤活性。与此同时，DzMN也通过搭乘（此处原文似乎有缺失内容）被递送至肿瘤，在肿瘤细胞内化后可释放Dz和Mn。然后Dz被其Mn辅助因子激活以切割靶标PD-L1 mRNA，从而作为一种自我激活的基因沉默系统。分别将（此处原文似乎有缺失内容）和Dz用于免疫激活和PD-L1敲低，实现了具有增强疗效的抗肿瘤免疫治疗。值得注意的是，PST包被可显著降低（此处原文似乎有缺失内容）在正常器官的感染潜力和非特异性定植，实现高体内生物安全性。这项工作通过生物材料修饰解决了（此处原文似乎有缺失内容）在体内应用的关键局限性，并为更好的微生物免疫治疗提供了一个有前景的平台。
