合成生物学与纳米生物学的交叉融合及其在生物医药领域的应用

doi:10.12211/2096-8280.2022-008

合成生物学 ›› 2022, Vol. 3 ›› Issue (2): 279-301.DOI: 10.12211/2096-8280.2022-008

合成生物学与纳米生物学的交叉融合及其在生物医药领域的应用

郑涵奇¹, 吴晴¹, 李洪军¹^,², 顾臻¹^,²^,³^,⁴

^1.浙江省先进递药系统重点实验室，浙江大学药学院，浙江杭州 310058
^2.浙江省系统与精准医学实验室，良渚实验室，浙江大学医学中心，浙江杭州 311121
^3.浙江大学医学院附属邵逸夫医院，普外科，浙江杭州 310016
^4.高分子合成与功能化教育部重点实验室，浙江大学高分子科学与工程系，浙江杭州 310027

收稿日期:2022-01-27 修回日期:2022-02-21 出版日期:2022-04-30 发布日期:2022-05-11
通讯作者: 李洪军,顾臻
作者简介:郑涵奇（2000—），男，硕士研究生。研究方向为新型工程化免疫细胞及其在肿瘤免疫治疗中的应用。 E-mail：zhenghanqi@zju.edu.cn
李洪军（1989—），男，浙江大学特聘研究员，博士生导师。研究方向包括新型工程化免疫细胞用于肿瘤免疫治疗的开发、智能型药物递送系统/器件的开发等。 E-mail：hongjun@zju.edu.cn
顾臻（1980—），男，浙江大学求是讲席教授、药学院院长，教育部“长江学者”讲席教授，浙江省先进递药系统重点实验室主任，国家重点研发计划项目首席科学家，博士生导师。研究方向包括蛋白质/核酸递药系统、生理响应材料、免疫治疗制剂、细胞治疗策略等。 E-mail：guzhen@zju.edu.cn
基金资助:
国家重点研发计划(2021YFA0909900);国家自然科学基金(52173142);浙江大学科研启动经费

Integration of synthetic biology and nanobiotechnology for biomedical applications

Hanqi ZHENG¹, Qing WU¹, Hongjun LI¹^,², Zhen GU¹^,²^,³^,⁴

^1.Zhejiang Provincial Key Laboratory for Advanced Drug Delivery Systems，College of Pharmaceutical Sciences，Zhejiang University，Hangzhou 310058，Zhejiang，China
^2.Zhejiang Laboratory of Systems & Precision Medicine，Liangzhu Laboratory，Zhejiang University Medical Center，Hangzhou 311121，Zhejiang，China
^3.Department of General Surgery，Sir Run Run Shaw Hospital，School of Medicine，Zhejiang University，Hangzhou 310016，Zhejiang，China
^4.MOE Key Laboratory of Macromolecular Synthesis and Functionalization，Department of Polymer Science and Engineering，Zhejiang University，Hangzhou 310027，Zhejiang，China

Received:2022-01-27 Revised:2022-02-21 Online:2022-04-30 Published:2022-05-11
Contact: Hongjun LI, Zhen GU

摘要/Abstract

摘要：

合成生物学与纳米生物学的交叉融合业已成为促进生物技术与生物医药领域发展的重要方向之一。利用合成生物学技术可以帮助生物源性纳米材料创造特殊的结构与功能，驱动纳米生物学的发展。纳米技术的应用则可助力基因线路递送，提升基于合成生物学的生产效率；参与介导基因调控，拓展合成生物学技术的应用场景。合成生物学和纳米生物学的融合可以构建出纳米级功能模块和纳米人工杂合系统，增强改造后体系的功能。本文将着重介绍近期合成生物学和纳米生物学交叉融合的相关研究进展，从纳米技术为合成生物学的发展赋能、合成生物学成为助力纳米技术应用的新引擎以及合成生物学和纳米生物学融合发展这三个角度，着重阐述该领域近期的重点工作，剖析并展望相关技术在基因编辑、药物递送以及医学成像等生物医药领域的应用和前景。未来，合成生物学和纳米生物学的交叉融合可能朝着模块化、标准化、仿生化、功能集成化和智能化的方向进一步发展，为生物医药领域带来新的突破。

关键词: 纳米技术, 合成生物学, 仿生, 基因工程, 药物递送

Abstract:

Synthetic biology aims at designing, transforming, and even re-synthesizing living organisms with specific functions. Nanobiotechnology is devoted to solving major biological problems through drug delivery and disease diagnosis and intervention by utilizing the unique physical, chemical and biological properties of substances at micro-and nano-scales. The integration of synthetic biology and nanobiotechnology promotes the fundamental and clinical development of biomedical science and biotechnology. Nanomaterials obtained through synthetic biology technology could be endowed with unique structures and functions, facilitating the advances of nanobiology. The application of nanotechnology can expand the application scenarios of synthetic biotechnology, improve the production efficiency of target compounds, and enhance the functions of modified organisms. This review focuses on the recent research progress in the interdisciplinary field of synthetic biology and nanobiotechnology from three perspectives, including (1) how can nanotechnology reinforce the development of synthetic biology? (2) how can synthetic biology extend the applications of nanotechnology? (3) how can synthetic biology and nanobiology jointly work to bring in new techniques? Specifically, the nanocarriers can enhance the delivery efficiency of synthetic gene circuits and genome editing agents. The ability to realize the signal transduction of nanoparticles can enable the spatiotemporal control of gene expression via minimally invasive manipulations. The biologic nano-agents strengthened by genetic engineering have been developed, such as the programmed cell-derived particles, including exosomes, microvesicles, and membrane-derived particles. Under the guidance of the philosophy of synthetic biology, modular functional nanocomponents can be formulated by self-assembly on the basis of nucleic acids, proteins, lipids, polymers, and inorganic materials. The nanodevices and engineered biological chassis can benefit the hybrid system through taking advantage of both sides. Furthermore, we also discuss the applications and prospects of related technologies mentioned above in genome editing, drug delivery, diseases diagnosis, and other biomedical fields. At the disciplinary crossroad, the integration of synthetic biology and nanobiotechnology can drive towards modularization, standardization, bioinspiration, functional integration, and intelligentization for next-generation biomedical breakthroughs. Representative examples for the integration of synthetic biology and nanobiotechnology. Nanotechnology can reinforce the development of synthetic biology by promoting the design and delivery of gene circuits. The delivery of gene circuits can be facilitated by nanocarriers, including organic (a), inorganic (b), and bionic (c) systems. Nanoparticles can convert optical, magnetic, and acoustic signals to thermal signals to regulate gene expression (d). Synthetic biology can extend the applications of nanotechnology through genetically engineering biologic nano-agents. Platelets (e), exosomes (f), microvesicles (g), and membrane-derived vesicles (h) can be programmed through synthetic biology. Synthetic biology and nanobiology can jointly generate functional modules and hybrid systems for artificial biomimetic systems. DNA, lipids, and polymers can self-assemble into functional modules (i), and nanoparticles can be combined with chimeric antigen receptor T-cells and bacteria respectively to form hybrid systems (j).

Key words: nanotechnology, synthetic biology, bioinspired and biomimetic, genetic engineering, drug delivery

中图分类号:

Q 819

郑涵奇, 吴晴, 李洪军, 顾臻. 合成生物学与纳米生物学的交叉融合及其在生物医药领域的应用[J]. 合成生物学, 2022, 3(2): 279-301.

Hanqi ZHENG, Qing WU, Hongjun LI, Zhen GU. Integration of synthetic biology and nanobiotechnology for biomedical applications[J]. Synthetic Biology Journal, 2022, 3(2): 279-301.

图/表 7

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载体类型	载体材料	递送目标类别	特征	参考文献
有机纳米载体	两性离子氨基脂质纳米颗粒	长RNA（含Cas9 mRNA、sgRNA）	可以将多个长RNA打包递送，有望提供DNA修复模板来介导HDR（同源介导的双链DNA修复）基因校正	[36]
	基于卵磷脂的纳米脂质体	Cas9/sgRNA RNP	高生物相容性、低细胞毒性和高溶液稳定性	[35]
	基于可电离脂质的脂质纳米颗粒	Cas9-sgRNA质粒	促进膜融合、膜破裂和内涵体逃逸	[37]
	可生物还原的脂质纳米颗粒	Cas9/sgRNA RNP， Cas9 mRNA/sgRNA	响应还原性细胞内环境，更有效释放RNA和蛋白质	[40-41]
	转铁蛋白修饰的脂质体	DNA	将功能蛋白的肿瘤靶向潜力和优异的基因递送性能相结合	[42]
	超支化阳离子聚（β-氨基酯）	Cas9/sgRNA RNP	能以不同表面电荷实现分子量在一定范围内的蛋白质的胞质递送	[48]
	氟化酸不稳定支链富羟基聚阳离子	Cas9-sgRNA质粒	良好的pH响应降解性、生物相容性	[51]
	乳糖衍生的支链阳离子生物聚合物	Cas9-sgRNA质粒	优异的降解性、生物相容性、基因转染性能和肝癌细胞靶向能力	[52]
	聚（二硫化物）	DNA、mRNA和RNP三种形式的CRISPR-Cas9	极大限度地减少了不可降解聚合物载体常见的细胞毒性	[54]
	阳离子α-螺旋多肽	Cas9质粒/sgRNA	具有作为高效基因载体和细胞膜穿透剂的双重功能	[53]
无机纳米载体	金纳米粒	Cas9/sgRNA RNP，DNA， Cas9-sgRNA质粒	具有独特的光学和结构特性，可以作为基因递送的多功能平台	[65-66,70]
	镧系元素掺杂的上转换纳米粒子	Cas9/sgRNA RNP	作为纳米传感器，可以通过光来远程控制基因编辑工具的释放	[71]
	纳米级沸石咪唑骨架	质粒DNA，Cas9/sgRNA RNP	在内涵体pH下质子化，促进内涵体逃逸，增强了向细胞核的递送	[72,74]
	功能化的介孔二氧化硅颗粒	Cas9/sgRNA RNP	具有高表面积和可调节的孔径，可以和修饰硼酸基团的蛋白质形成配位和静电相互作用，提高向细胞内递送的效率	[79]
生物仿生纳米载体	细胞膜衍生纳米囊泡	质粒cDNA	MSC纳米囊泡具有生物相容性，并保留了MSC对各种肿瘤细胞的表面相关靶向能力	[84]
	细胞外囊泡	CRISPR/Cas9质粒，Cas9/sgRNA RNP	可以被修饰改造以实现靶向递送	[90-91]
	DNA纳米线球	Cas9/sgRNA RNP	DNA纳米线球和sgRNA引导序列之间部分互补时能实现更高效率的基因编辑	[28]
	病毒样颗粒	Cas9/sgRNA RNP	实现瞬时快速递送，并降低脱靶率	[87-88]

载体类型	载体材料	递送目标类别	特征	参考文献
有机纳米载体	两性离子氨基脂质纳米颗粒	长RNA（含Cas9 mRNA、sgRNA）	可以将多个长RNA打包递送，有望提供DNA修复模板来介导HDR（同源介导的双链DNA修复）基因校正	[36]
	基于卵磷脂的纳米脂质体	Cas9/sgRNA RNP	高生物相容性、低细胞毒性和高溶液稳定性	[35]
	基于可电离脂质的脂质纳米颗粒	Cas9-sgRNA质粒	促进膜融合、膜破裂和内涵体逃逸	[37]
	可生物还原的脂质纳米颗粒	Cas9/sgRNA RNP， Cas9 mRNA/sgRNA	响应还原性细胞内环境，更有效释放RNA和蛋白质	[40-41]
	转铁蛋白修饰的脂质体	DNA	将功能蛋白的肿瘤靶向潜力和优异的基因递送性能相结合	[42]
	超支化阳离子聚（β-氨基酯）	Cas9/sgRNA RNP	能以不同表面电荷实现分子量在一定范围内的蛋白质的胞质递送	[48]
	氟化酸不稳定支链富羟基聚阳离子	Cas9-sgRNA质粒	良好的pH响应降解性、生物相容性	[51]
	乳糖衍生的支链阳离子生物聚合物	Cas9-sgRNA质粒	优异的降解性、生物相容性、基因转染性能和肝癌细胞靶向能力	[52]
	聚（二硫化物）	DNA、mRNA和RNP三种形式的CRISPR-Cas9	极大限度地减少了不可降解聚合物载体常见的细胞毒性	[54]
	阳离子α-螺旋多肽	Cas9质粒/sgRNA	具有作为高效基因载体和细胞膜穿透剂的双重功能	[53]
无机纳米载体	金纳米粒	Cas9/sgRNA RNP，DNA， Cas9-sgRNA质粒	具有独特的光学和结构特性，可以作为基因递送的多功能平台	[65-66,70]
	镧系元素掺杂的上转换纳米粒子	Cas9/sgRNA RNP	作为纳米传感器，可以通过光来远程控制基因编辑工具的释放	[71]
	纳米级沸石咪唑骨架	质粒DNA，Cas9/sgRNA RNP	在内涵体pH下质子化，促进内涵体逃逸，增强了向细胞核的递送	[72,74]
	功能化的介孔二氧化硅颗粒	Cas9/sgRNA RNP	具有高表面积和可调节的孔径，可以和修饰硼酸基团的蛋白质形成配位和静电相互作用，提高向细胞内递送的效率	[79]
生物仿生纳米载体	细胞膜衍生纳米囊泡	质粒cDNA	MSC纳米囊泡具有生物相容性，并保留了MSC对各种肿瘤细胞的表面相关靶向能力	[84]
	细胞外囊泡	CRISPR/Cas9质粒，Cas9/sgRNA RNP	可以被修饰改造以实现靶向递送	[90-91]
	DNA纳米线球	Cas9/sgRNA RNP	DNA纳米线球和sgRNA引导序列之间部分互补时能实现更高效率的基因编辑	[28]
	病毒样颗粒	Cas9/sgRNA RNP	实现瞬时快速递送，并降低脱靶率	[87-88]

细菌	细菌改造	修饰纳米材料	效能	参考文献
Magnetococcus marinus MC-1	包含一串磁性氧化铁纳米晶体	含药物纳米脂质体	磁引导细菌将含药纳米脂质体运输到SCID Beige小鼠HCT116异种移植结直肠肿瘤的缺氧区	[162]
S. typhimurium VNP20009	兼性厌氧，减毒营养缺陷型突变体	PLGA纳米粒	将纳米颗粒在BALB/c小鼠的4T1乳腺癌原位模型中的保留和分布提高100倍	[168]
S. typhimurium ELH1301， E. coli Nissle 1917	具有编码气体囊泡的工程基因簇	蛋白质外壳的纳米气体囊泡	超声波报告基因工程，用于超声成像	[165]
E. coli MG1655	过表达呼吸链酶Ⅱ（NDH-Ⅱ）	磁性Fe₃O₄纳米粒子	在BALB/c小鼠的CT 26结肠癌部位原位催化产生H₂O₂，诱导肿瘤细胞死亡	[169]
E. coli MG1655	表达硝酸盐/亚硝酸盐还原酶	碳点掺杂氮化碳	光控细菌代谢物疗法，光照射下生成NO抑制BALB/c小鼠4T1肿瘤生长	[161]
E. coli	过表达过氧化氢酶	含Ce6涂层的聚多巴胺纳米粒	NIR光照射下实现光热疗法和光动力疗法，在荷瘤BALB/c裸鼠中抑制肿瘤生长	[166]
S. typhimurium YB1	缺氧靶向	载有吲哚菁绿（ICG）的纳米颗粒	在NIR激光照射下，产生光热杀伤能力，根除C57 BL/6小鼠的MB49实体瘤	[160]
Magnetococcus marinus AMB-1	趋磁性和缺氧靶向	光触发的吲哚菁绿纳米粒子	磁驱动富集到肿瘤部位，光热疗法消除MCF-7荷瘤BALB/c裸鼠中的肿瘤	[170]

细菌	细菌改造	修饰纳米材料	效能	参考文献
Magnetococcus marinus MC-1	包含一串磁性氧化铁纳米晶体	含药物纳米脂质体	磁引导细菌将含药纳米脂质体运输到SCID Beige小鼠HCT116异种移植结直肠肿瘤的缺氧区	[162]
S. typhimurium VNP20009	兼性厌氧，减毒营养缺陷型突变体	PLGA纳米粒	将纳米颗粒在BALB/c小鼠的4T1乳腺癌原位模型中的保留和分布提高100倍	[168]
S. typhimurium ELH1301， E. coli Nissle 1917	具有编码气体囊泡的工程基因簇	蛋白质外壳的纳米气体囊泡	超声波报告基因工程，用于超声成像	[165]
E. coli MG1655	过表达呼吸链酶Ⅱ（NDH-Ⅱ）	磁性Fe₃O₄纳米粒子	在BALB/c小鼠的CT 26结肠癌部位原位催化产生H₂O₂，诱导肿瘤细胞死亡	[169]
E. coli MG1655	表达硝酸盐/亚硝酸盐还原酶	碳点掺杂氮化碳	光控细菌代谢物疗法，光照射下生成NO抑制BALB/c小鼠4T1肿瘤生长	[161]
E. coli	过表达过氧化氢酶	含Ce6涂层的聚多巴胺纳米粒	NIR光照射下实现光热疗法和光动力疗法，在荷瘤BALB/c裸鼠中抑制肿瘤生长	[166]
S. typhimurium YB1	缺氧靶向	载有吲哚菁绿（ICG）的纳米颗粒	在NIR激光照射下，产生光热杀伤能力，根除C57 BL/6小鼠的MB49实体瘤	[160]
Magnetococcus marinus AMB-1	趋磁性和缺氧靶向	光触发的吲哚菁绿纳米粒子	磁驱动富集到肿瘤部位，光热疗法消除MCF-7荷瘤BALB/c裸鼠中的肿瘤	[170]

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合成生物学与纳米生物学的交叉融合及其在生物医药领域的应用

Integration of synthetic biology and nanobiotechnology for biomedical applications

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