合成生物学赋能细胞膜纳米颗粒的精准诊疗

doi:10.12211/2096-8280.2025-069

合成生物学

• 特约评述 •

合成生物学赋能细胞膜纳米颗粒的精准诊疗

黄扬¹^,², 李一叶¹^,³, 聂广军¹^,²^,³

^1.国家纳米科学中心，中国科学院纳米生物效应与安全性重点实验室，中国科学院纳米科学卓越创新中心，北京，100190
^2.中国科学院大学，纳米科学与工程学院，北京，100049
^3.中国科学院大学，材料科学与光电技术学院，北京，100049

收稿日期:2025-06-30 修回日期:2025-07-23 出版日期:2025-07-28
通讯作者: 李一叶,聂广军
作者简介:黄扬（2001—），女，硕士研究生，研究方向为纳米材料在骨相关疾病中的应用。E-mail：huangy2023@nanoctr.cn
李一叶（1977—），女，博士，研究员，研究方向为纳米生物医学与纳米药物。E-mail：liyy@nanoctr.cn
聂广军（1974—），男，博士，研究员，研究方向为纳米生物学与智能纳米药物。 E-mail：niegj@nanoctr.cn
基金资助:
国家自然科学基金(2021YFA1201103);国家自然科学基金(2023YFC2509900)

Synthetic Biology-Powered Cell Membrane-Derived Nanoparticles for Precision Theranostics

HUANG Yang¹^,², LI Yiye¹^,³, NIE Guangjun¹^,²^,³

^1.CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety，CAS Center for Excellence in Nanoscience，National Center for Nanoscience and Technology of China，Beijing 100190，China
^2.School of Nanoscience and Engineering，University of Chinese Academy of Sciences，Beijing 100049，China
^3.College of Materials Science and Opto-Electronic Technology，University of Chinese Academy of Sciences，Beijing 100049，China

Received:2025-06-30 Revised:2025-07-23 Online:2025-07-28
Contact: LI Yiye, NIE Guangjun

摘要/Abstract

摘要：

细胞膜纳米颗粒（cell membrane-derived nanoparticles， CNPs）能够有效整合天然细胞膜的生物学特性和纳米材料的理化性质，在疾病诊疗研究中展现出循环时间长、生物相容性好和靶向特异性强等优势；但其临床应用受限于天然膜的异质性和功能局限性。合成生物学为突破这一瓶颈提供了创新性策略，驱动CNPs实现从天然仿生到精准设计的范式转变。基因工程技术通过物理、化学及生物学手段精准编辑细胞膜蛋白表达，而代谢工程技术通过糖类和脂质代谢等通路实现细胞膜表面功能分子的定向锚定，从而赋予CNPs增强的靶向特异性、智能响应性与多功能协同性，使其在恶性肿瘤、心血管疾病和感染性疾病等多种疾病领域展现出巨大潜力。尽管在安全性评估、规模化生产和监管框架构建等方面仍面临挑战，但随着人工智能辅助设计、新型基因编辑和代谢介入技术的发展以及标准化生产平台的建立，合成生物学赋能的CNPs有望实现从实验室研究向临床应用的跨越，发展成为助力精准医疗的智能纳米诊疗平台。

关键词: 细胞膜纳米颗粒, 合成生物学, 基因工程, 代谢工程, 精准医疗

Abstract:

Cell membrane-derived nanoparticles (CNPs) integrate the biological characteristics of natural cell membranes (e.g., immune evasion, lesion targeting and immune modulation) with the tailorable physicochemical properties of synthetic nanomaterials, demonstrating significant advantages such as prolonged circulation, high biocompatibility, and specific targeting in disease diagnosis and treatment. However, their clinical application is limited by the inherent heterogeneity and functional limitations of natural membranes, including restricted targeting specificity, uncontrollable responsiveness, and lack of functionality. Synthetic biology provides innovative strategies to overcome these bottlenecks, driving a paradigm shift in CNPs from natural biomimicry to precise design. Genetic engineering enables precise editing of cell membrane protein expression via physical (e.g., electroporation, microinjection and gene gun), chemical (cationic lipids/polymers), and biological (viral vectors) strategies. Concurrently, metabolic engineering regulates the directional anchoring of functional moieties on cell membrane through manipulating cells' natural biosynthetic pathways, such as glycan (sialic acid and N-acetylgalactosamine (GalNAc) salvage pathways) and lipid (cytidine 5'-diphosphocholine pathway) metabolism. These approaches endow CNPs with enhanced targeting specificity, intelligent responsiveness (e.g., pH/enzyme/light-triggered drug release), and multifunctional synergy, enabling them to demonstrate significant therapeutic potential across diverse diseases including malignant tumors, cardiovascular diseases, and infectious diseases. In oncology, synthetic CNPs (SCNPs) deliver chemotherapeutics, radiotherapy sensitizers and contrast agents with tumor-homing specificity and enable innovative immunotherapies by presenting checkpoint inhibitors, tumor antigens or adjuvants. For cardiovascular diseases, SCNPs demonstrate remarkable inflammatory targeting and alleviation capabilities. In infectious diseases, SCNPs neutralize toxins, bacteria and viruses as broad-spectrum "nanosponges", while antigen-presenting SCNPs act as potent vaccines. Applications of SCNPs extend to autoimmune conditions, neurodegenerative disorders and bone-related diseases. Although challenges remain in safety assessment, scalable manufacturing, and regulatory frameworks, advances in artificial intelligence-assisted rational design, novel gene editing tools (e.g., prime editing) for safer genomic modifications, metabolic intervention technologies optimizations, alongside the establishment of standardized production platforms, are poised to bridge the gap between laboratory and clinic. Ultimately, synthetic biology-powered CNPs are anticipated to evolve into intelligent nano-theranostic platformsfacilitating precision medicine.

Key words: cell membrane-derived nanoparticles, synthetic biology, genetic engineering, metabolic engineering, precision medicine

中图分类号:

Q816

黄扬, 李一叶, 聂广军. 合成生物学赋能细胞膜纳米颗粒的精准诊疗[J]. 合成生物学, DOI: 10.12211/2096-8280.2025-069.

HUANG Yang, LI Yiye, NIE Guangjun. Synthetic Biology-Powered Cell Membrane-Derived Nanoparticles for Precision Theranostics[J]. Synthetic Biology Journal, DOI: 10.12211/2096-8280.2025-069.

图/表 12

图1 NCNPs的制备。通过Biorender绘制。NCNPs的制备主要分为三个步骤：（1）天然细胞膜的提取，主要技术包括低渗裂解、反复冻融、超声和均质化；（2）纳米核心的制备；（3）细胞膜与纳米核心的融合，主要技术包括挤压法、超声处理和电穿孔。

Fig. 1 Preparation of NCNPs. Created in BioRender. Huang Yang (2025)[The preparation of NCNPs usually involves three steps: (1) natural cell membrane extraction, mainly involves techniques such as hypotonic lysis, freeze-thawing, ultrasonic waves, and homogenization; (2) preparation of nanocores; (3) fusion of cell membrane and nanocore, mainly involves techniques such as extrusion, sonication, and electroporation.]

图2 SCNPs的功能化策略。通过Biorender绘制主要包括：（1）脂质插入：通过脂质锚将功能配体结合到天然细胞膜上；（2）膜杂交：通过从单个细胞类型中提取膜后融合，或融合不同的活细胞然后从杂交细胞中提取膜；（3）基因工程：通过选择性基因编辑改变细胞表面的蛋白质表达；（4）代谢工程：将功能部分与代谢底物结合，通过天然代谢途径将其锚定在细胞表面。

Fig. 2 Engineering strategies for SCNPs. Created in BioRender. Huang Yang (2025)[Mainly includes: (1) lipid insertion, which incorporates functional ligands onto natural cell membranes through a lipid anchor;(2) membrane hybridization, which derives the membrane from individual cell types and then fuse them or fuses different live cells and then derives membrane from the cell hybrids;(3) genetic engineering, which alters protein expression on the cell surfaces through selective gene editing and (4) metabolic engineering, which conjugates functional moieties with metabolic substrates to anchor them to the cell surfaces through natural metabolic pathways.]

图3 基因转染策略。通过Biorender绘制主要包括物理策略（如：电/超声/激光辅助穿孔、基因枪和显微注射等）、化学策略（如：阳离子脂质/聚合物介导的跨膜运输等）和生物策略（如：病毒转导等）。

Fig. 3 Strategies of gene transfection. Created in BioRender. Huang Yang (2025)[It mainly includes physical strategies (e.g., electricity/ultrasound/laser -assisted perforation, gene gun and microinjection), chemical strategies (e.g., cationic lipids/polymers -mediated transmembrane transport), and biological strategies (e.g., viral transduction).]

表1 基因工程化细胞膜纳米颗粒的生物医学应用

Table 1 Biomedical applications of nanoparticles with genetically engineered membranes

基因递送载体		细胞膜来源	特异表达蛋白	生物医学应用	参考文献
病毒载体	逆转录病毒载体	脂肪来源干细胞	CXCR4	通过CXCR4/SDF-1靶向炎症部位	[76]
	慢病毒载体	RAW 264.7	CCR2	通过CCR2/CCL2靶向炎症部位，阻断炎症信号，缓解炎症	[77]
		LX2	TRAIL	通过TRAIL-受体相互作用诱导肿瘤细胞凋亡	[80]
		神经干细胞	CXCR4	通过CXCR4/SDF-1靶向炎症部位，跨越血脑屏障	[82]
		CT26	HER2抗体	通过HER2抗体/HER靶向肿瘤部位，激活肿瘤免疫	[19]
		RAW 264.7	HA，RAGE	通过RAGE/S100A9靶向炎症受损心肌，缓解炎症和心肌损伤；通过HA实现内体逃逸	[81]
	腺病毒载体	DCs	MHC-I，PD 1，B7	通过MHC-I/PD-1/B7活化T细胞，激活肿瘤免疫	[79]
	腺病毒载体	神经干细胞	Lamp 2b-RVG	通过RVG/乙酰胆碱受体靶向神经细胞，跨越血脑屏障	[78]
非病毒载体	阳离子脂质体	B16-F10	卵清白蛋白，CD80	通过卵清白蛋白/CD80活化T细胞，激活肿瘤免疫	[31]
		B16-F10	HA	通过HA实现内体逃逸	[86]
		C1498	VLA-4	通过VLA-4/VCAM-1靶向炎症部位	[39]
		HEK293T	PD-1	通过PD-1/PD-L1靶向肿瘤部位，阻断免疫检查点，激活肿瘤免疫	[75]
	阳离子聚合物	4T1-Fluc	KillerRed	通过KillerRed实现光动力治疗，杀伤肿瘤	[73]
	阳离子聚合物	B16-F10	CD 47 KO/CRT	激活肿瘤免疫	[74]

表2 代谢工程化细胞膜纳米颗粒的合成及生物医学应用

Table 2 Biomedical applications and synthesis of nanoparticles with metabolically engineered membranes

代谢工程	生物合成途径	代谢底物	生物医学应用	参考文献
糖工程	唾液酸途径	N-乙酰甘露糖胺 ManNAc	插入N₃偶联肝素，中和SARS-CoV-2	[87]
		N-叠氮基乙酰基甘露糖胺 ManNAz	插入N₃偶联抗 CD3ε抗体，激活肿瘤免疫	[88]
			插入N₃，增强细胞膜-纳米核结合	[89]
			插入N₃偶联ALN，靶向骨组织	[90]
	GalNAc补救合成途径	N-乙酰半乳糖胺 GalNAc	插入N₃，靶向肿瘤细胞BCN	[91]
脂质工程	CDP-胆碱途径	胆碱 Choline	插入N₃偶联RGD，靶向肿瘤	[35]
			插入N₃偶联pMHC-I/CD28，激活肿瘤免疫	[92]
			插入N₃偶联抗CD205，激活肿瘤免疫	[93]

图4 N3-标记的T 细胞膜仿生纳米颗粒双靶向机制示意图［91］A） N3-TINPs的合成。B）通过Ac4ManN-BCN预处理进行天然糖代谢标记，使肿瘤细胞携带BCN基团。N3-TINPs可通过T细胞膜的免疫识别以及BCN与N3基团之间的生物正交反应靶向肿瘤。

Fig. 4 Schematic illustration of N3-labeled T cell membrane-biomimetic nanoparticles with dual-targeting mechanism [91][A) Synthesis of N3-TINPs. B) Tumor cells carrying the BCN group via natural glycometabolic labeling by pretreatment with Ac4ManN-BCN. N3-TINPs could target tumor through immune recognition of T cell membrane and bioorthogonal reaction between BCN and N3 groups.]

图5 SCNPs的合成生物学赋能。通过Biorender绘制。

Fig. 5 Additional functions of SCNPs enabled by synthetic biology. Created in BioRender. Huang Yang (2025).

表3 SCNPs在疾病诊疗中的主要应用

Table 3 The application of SCNPs in disease diagnosis and treatment

应用	功能	机制	参考文献
恶性肿瘤	肿瘤靶向	修饰靶向分子，如RGD、NGR	[110,35]
	免疫疗法	表达免疫检测点抗体或受体，阻断PD-1/PD-L1 信号轴；	[61,75]
	免疫疗法	修饰肿瘤抗原和/或肿瘤细胞膜固有抗原激活肿瘤免疫，发挥疫苗功效	[79]
心血管疾病	炎症靶向和缓解	修饰靶向蛋白如VLA-4；血小板、巨噬细胞等固有炎症靶向和免疫调节能力	[111,112,81]
感染性疾病	中和病原体	修饰对应受体/配体/抗体，如肝素	[87,106]
感染性疾病	激活免疫应答	展示病毒特异性抗原表位	[113]
自身免疫性疾病	抑制免疫激活	修饰对应受体，如OX40、CD40，阻断免疫激活信号	[114]
神经退行性疾病	跨越血脑屏障实现靶向递送	神经干细胞脑归巢效应；修饰靶向分子，如CCR2	[78,115]
骨相关疾病	骨靶向	修饰靶向分子，如CXCR4、ALN	[90,116]
骨相关疾病	中和破骨因子	过表达对应受体，如RANK	[117]

图6 具有增强PD-1表达的工程化巨噬细胞膜纳米颗粒的合成示意图［61］巨噬细胞膜纳米颗粒穿透血脑屏障实现药物靶向递送；膜上原位工程化的PD-1过表达竞争性结合PD-L1，有效阻断PD-1/PD-L1信号轴。

Fig. 6 Schematic Illustration of Preparing Engineered Macrophage-Membrane-Coated Nanoparticles with Enhanced PD-1 Expression[61][Macrophage membrane-derived NPs permeate the blood-brain-barrier and conduct targeted drug delivery; in situ engineered overexpression of PD-1 on the macrophage membrane competitively binds to PD-L1 and effectively blocks the PD-1/PD-L1 signaling axis.]

图7 巨噬细胞细胞膜纳米颗粒介导的siRNA递送治疗心肌缺血再灌注损伤的示意图［81］A） MMM/RNA纳米颗粒制备示意图。通过编码HA和RAGE的腺病毒转染构建工程化巨噬细胞。B）心肌缺血再灌注小鼠尾静脉注射MMM/RNA纳米颗粒示意图。心肌缺血性损伤会吸引大量血液中的中性粒细胞，这些中性粒细胞被激活并释放S100A9炎症因子。MMM/RNA纳米颗粒通过膜蛋白RAGE沿S100A9浓度梯度聚集到心肌损伤区域。MMM/RNA纳米颗粒被中性粒细胞吞噬，并通过膜蛋白HA实现内体逃逸，将siRNA转运到细胞质中。

Fig.7 Schematic representation of MMM/RNA NPs-mediated siRNA delivery for the treatment of MIRI[81][A) Depiction of the MMM/RNA NPs preparation. Macrophages were transfected with adenoviruses encoding for HA and RAGE to construct engineered macrophages. B) Diagram of MMM/RNA NPs injected into the tail vein of myocardial ischemia-reperfusion mice. Myocardial ischemic injury recruits a large number of neutrophils in the blood, which activate and release S100A9 inflammatory factors. MMM/RNA NPs rely on their cell membrane protein RAGE to recruit to the myocardial injury area along the concentration of S100A9. Neutrophils engulf MMM/RNA NPs, and MMM/RNA NPs rely on their cell membrane protein HA to play an endosomal escape role, transporting siRNA to the cytoplasm.]

图8 纳米海绵抵抗新冠肺炎示意图［106］A）通过融合源自基因编辑的293T/ACE2和THP-1细胞的细胞膜纳米囊泡来制备纳米海绵。纳米海绵展示丰富的ACE2和细胞因子受体，与宿主细胞竞争结合（B） SARS-CoV-2和（C）炎症因子（如IL-6和GM-CSF）。

Fig. 8 Schematic illustration of nanosponges against COVID-19[106][A) Preparation of nanosponges by fusing cellular membrane nanovesicles derived from genetically edited 293T/ACE2 and THP-1 cells. The nanosponges, displaying abundant ACE2 and cytokine receptors, compete with host cells to bind (B) SARS-CoV-2 and (C) inflammatory cytokines, such as IL-6 and GM-CSF.]

图9 SCNPs的规模化生产流程。通过Biorender绘制。

Fig. 9 The scale production process of SCNPs. Created in BioRender. Huang Yang (2025).

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合成生物学赋能细胞膜纳米颗粒的精准诊疗

Synthetic Biology-Powered Cell Membrane-Derived Nanoparticles for Precision Theranostics

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