细胞壳化：基于表面工程的细胞功能化
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摘要
在自然界的生物进化中,从最基本的单细胞生物到具有复杂多级结构的高等生物,大自然给我们呈现了多尺度、多层次的材料、结构,系统和功能。比如,许多单细胞的生物体表面具有一层可以作为生物矿化模板的蛋白质薄膜。以这个蛋白质薄膜为模板诱导生成的生物体矿化层可以作为一个功能化的保护外壳。众所周知,鸡蛋壳可以保护鸡蛋免受外界细菌的侵扰和外力的损伤。
在自然界中广泛分布的植物——硅藻也有一层具有多种图案化的矿化外壳。它的机械保护功能近日已被科学家们证实。但是,自然界中并不是所有的细胞都具有这样一个外壳。在这篇论文中,我们发展了一种给细胞制造外壳的策略,并初步探索了这种人造细胞外壳的工程技术在生物医学、生态环境保护以及可持续发展中的应用。
我们发展了一种在酵母细胞(Saccharomyces cerevisiae)表面诱导成壳的方法。通过层层自组装引入矿化位点和生理条件下的原位矿化两步法,每一个单一的酵母细胞可以成功地被磷酸钙的矿化层包裹。包裹后的酵母细胞依然保持良好的生理活性,被包裹后的细胞自动进入静止期(G0)并且他们的生命周期相应地被延长。矿化壳可以保护细胞在恶劣环境下存活,使细胞免受酵母裂解酶的消化裂解。矿化壳也可以作为对单细胞进行化学和生物功能改造的支架。例如,当我们把四氧化三铁颗粒整合在矿化壳中后,酵母细胞立刻被改造成为磁性细胞。以上这些工作启示我们：基于单细胞的人工壳功能化改造策略在细胞种质储存、细胞作为治疗药物的输送以及活细胞的功能改造等方面有着巨大的潜能和广阔的应用前景。伴随着系统生物学和分子生物学,以及分子功能材料学的迅猛发展,通过仿生矿化的细胞功能化壳一定会孕育出新一代的“超级细胞”。
伴随着平流层中臭氧层浓度的降低,越来越多的具有生物破坏性的中波段紫外线(UVB,280-320 nm)抵达地球表面。具有环境破坏性的中波段紫外线严重影响着自然界中海洋生物的种群数量,这主要是由于海洋生物被日益增加的紫外线辐射影响了其正常的胚胎发育过程。受自然界中生物系统进化策略的启发,我们在斑马鱼的囊胚期(blastula period)在其浆膜的表面诱导沉积了一层可以吸收紫外线的外衣。短时间高功率和长时间低功率的紫外辐射实验显示,人工矿化壳可以有效屏蔽外界紫外线的辐射,包裹的胚胎可以在室内模拟臭氧层空洞环境下的紫外线强度辐射下完成正常的发育过程。而没有处理过的胚胎在相应的外界紫外线辐射强度增加的环境下不能存活下来。通过斑马鱼模型,我们认为基于功能材料的工程壳可以赋予生物体全新的功能,并帮助他们更好地应对日益变化的生态环境,同时这个策略也给生物学研究提供了一个非常规条件下人工保护生物体的方法。
在本文中,我们展示了在细胞表面诱导形成矿化壳的各种方法。所形成的矿化壳可以模仿细胞膜(或壁)的特征,例如半透膜的性质,或者通过人工定制各种非天然的材料来实现诸如抗紫外线的功能,这些功能可以为细胞提供更好地适应外界环境的策略。功能材料和细胞的复合可以整合不同的材料功能和活细胞所特有的生物功能,进而衍生出能量自给的微型反应器和传感器。这些创新型的能量自给的微型生物器将在生态环境保护和新能源发展方面存在广泛的应用前景。
与单细胞微生物、受精卵细胞不同,人体内的细胞并不是孤立存在的,而是由细胞外基质交联在一起的。细胞外基质为细胞提供特定的生理微环境,并通过各种信号传导调节着周围细胞间通讯和单细胞的动力学行为。基于肿瘤部位相对于正常组织高表达金属基质蛋白酶和转铁蛋白受体的微环境,我们发展了一种可局部注射的、酶响应的、可以靶向于肿瘤微环境的水凝胶体系。这种细胞响应的水凝胶体系在癌细胞分泌的金属基质蛋白酶存在下释放包裹在水凝胶中的转铁蛋白-阿霉素复合物。释放出来的复合物可以通过癌细胞表面高表达的转铁蛋白受体选择性靶向于癌细胞,同时减少抗癌药物(阿霉素)对正常细胞的毒副作用。这种可注射的水凝胶药物输送体系给我们提供了一个可以通过改变用于合成水凝胶的交联多肽的酶响应敏感性,以及不同时期肿瘤分泌的金属基质蛋白酶的浓度不同来相应调节药物释放动力学的程序化智能平台。
In all living organisms, whether very basic or highly complex, nature provides a multiplicity of materials, architectures, systems and functions. A number of unicellular organisms have an outer-surface proteinaceous membrane as a template for biomineralization. The resultant thin mineral layer is a functional covering. For example, the mineral shell can protect an egg from invasion from the exterior, and the diatom has an ornately patterned silicified shell that evolved as mechanical protection. But most cells in nature cannot make their own hard shells. Here we show a strategy to fashion an artificial shell for single cell so that it has extensive protection. The potential applications of shell engineering in the fields of biomedicine, protection of ecological environment and sustainable development are also illustrated in this article.
Individual Saccharomyces cerevisiae (S. cerevisiae) cells are coated with a uniform calcium mineral layer by first self-assembly of functional polymers (layer-by-layer technique, LbL) and then in situ mineralization under physiological conditions. The viability of the cells is maintained after the encapsulation. The enclosed cells become inert (stationary phase) and their lifetime can be extended. Furthermore, the mineral shell protects the cell under harsh conditions. The encapsulated S. cerevisiae can even survive the attack of the lytic enzyme zymolyase. The shell can also be used as a scaffold for chemical and biological functionalization. For example, S. cerevisiae becomes magnetic by the incorporation of Fe3O34 nanoparticles in the mineral layer. The present work demonstrates that the artificial shell has a great potential in the storage, protection, delivery, and modification of living cells. Furthermore, insights from systems biology combined with an understanding of the molecular mechanisms of functional shells will facilitate the tailoring of "super cells" through biomimetic mineralization.
Different from unicellular organisms and fertilized egg cells, cells inside human tissues are not separate but connected together by extracellular matrix (ECM). The ECM provides a physiological microenvironment for cells and regulates intercellular communication and a cell's dynamic behavior. Based on two over-expressed factors in the tumor microenvironment, matrix metalloproteinases (MMPs) and transferrin (TRF) receptors on the cell surfaces, we develop an enzyme-responsive locally injectable hydrogel system that target the tumor microenvironment. The cell-responsive hydrogel system is designed to release the encapsulated transferrin-drug conjugate in presence of MMPs secreted by cancer cells. The released conjugate is selectively targeted to tumor cells via receptor-mediated endocytosis by TRF receptors that are over-expressed in cancer cell, reducing nonspecific cytotoxicity to the normal cells. The injectable hydrogel drug-delivery system is minimally invasive, offering a highly tunable and programmable platform to modulate drug release through MMP crosslinker peptide sensitivity or tumor stage dependent MMP enzyme expression.
在自然界中广泛分布的植物——硅藻也有一层具有多种图案化的矿化外壳。它的机械保护功能近日已被科学家们证实。但是,自然界中并不是所有的细胞都具有这样一个外壳。在这篇论文中,我们发展了一种给细胞制造外壳的策略,并初步探索了这种人造细胞外壳的工程技术在生物医学、生态环境保护以及可持续发展中的应用。
我们发展了一种在酵母细胞(Saccharomyces cerevisiae)表面诱导成壳的方法。通过层层自组装引入矿化位点和生理条件下的原位矿化两步法,每一个单一的酵母细胞可以成功地被磷酸钙的矿化层包裹。包裹后的酵母细胞依然保持良好的生理活性,被包裹后的细胞自动进入静止期(G0)并且他们的生命周期相应地被延长。矿化壳可以保护细胞在恶劣环境下存活,使细胞免受酵母裂解酶的消化裂解。矿化壳也可以作为对单细胞进行化学和生物功能改造的支架。例如,当我们把四氧化三铁颗粒整合在矿化壳中后,酵母细胞立刻被改造成为磁性细胞。以上这些工作启示我们：基于单细胞的人工壳功能化改造策略在细胞种质储存、细胞作为治疗药物的输送以及活细胞的功能改造等方面有着巨大的潜能和广阔的应用前景。伴随着系统生物学和分子生物学,以及分子功能材料学的迅猛发展,通过仿生矿化的细胞功能化壳一定会孕育出新一代的“超级细胞”。
伴随着平流层中臭氧层浓度的降低,越来越多的具有生物破坏性的中波段紫外线(UVB,280-320 nm)抵达地球表面。具有环境破坏性的中波段紫外线严重影响着自然界中海洋生物的种群数量,这主要是由于海洋生物被日益增加的紫外线辐射影响了其正常的胚胎发育过程。受自然界中生物系统进化策略的启发,我们在斑马鱼的囊胚期(blastula period)在其浆膜的表面诱导沉积了一层可以吸收紫外线的外衣。短时间高功率和长时间低功率的紫外辐射实验显示,人工矿化壳可以有效屏蔽外界紫外线的辐射,包裹的胚胎可以在室内模拟臭氧层空洞环境下的紫外线强度辐射下完成正常的发育过程。而没有处理过的胚胎在相应的外界紫外线辐射强度增加的环境下不能存活下来。通过斑马鱼模型,我们认为基于功能材料的工程壳可以赋予生物体全新的功能,并帮助他们更好地应对日益变化的生态环境,同时这个策略也给生物学研究提供了一个非常规条件下人工保护生物体的方法。
在本文中,我们展示了在细胞表面诱导形成矿化壳的各种方法。所形成的矿化壳可以模仿细胞膜(或壁)的特征,例如半透膜的性质,或者通过人工定制各种非天然的材料来实现诸如抗紫外线的功能,这些功能可以为细胞提供更好地适应外界环境的策略。功能材料和细胞的复合可以整合不同的材料功能和活细胞所特有的生物功能,进而衍生出能量自给的微型反应器和传感器。这些创新型的能量自给的微型生物器将在生态环境保护和新能源发展方面存在广泛的应用前景。
与单细胞微生物、受精卵细胞不同,人体内的细胞并不是孤立存在的,而是由细胞外基质交联在一起的。细胞外基质为细胞提供特定的生理微环境,并通过各种信号传导调节着周围细胞间通讯和单细胞的动力学行为。基于肿瘤部位相对于正常组织高表达金属基质蛋白酶和转铁蛋白受体的微环境,我们发展了一种可局部注射的、酶响应的、可以靶向于肿瘤微环境的水凝胶体系。这种细胞响应的水凝胶体系在癌细胞分泌的金属基质蛋白酶存在下释放包裹在水凝胶中的转铁蛋白-阿霉素复合物。释放出来的复合物可以通过癌细胞表面高表达的转铁蛋白受体选择性靶向于癌细胞,同时减少抗癌药物(阿霉素)对正常细胞的毒副作用。这种可注射的水凝胶药物输送体系给我们提供了一个可以通过改变用于合成水凝胶的交联多肽的酶响应敏感性,以及不同时期肿瘤分泌的金属基质蛋白酶的浓度不同来相应调节药物释放动力学的程序化智能平台。
In all living organisms, whether very basic or highly complex, nature provides a multiplicity of materials, architectures, systems and functions. A number of unicellular organisms have an outer-surface proteinaceous membrane as a template for biomineralization. The resultant thin mineral layer is a functional covering. For example, the mineral shell can protect an egg from invasion from the exterior, and the diatom has an ornately patterned silicified shell that evolved as mechanical protection. But most cells in nature cannot make their own hard shells. Here we show a strategy to fashion an artificial shell for single cell so that it has extensive protection. The potential applications of shell engineering in the fields of biomedicine, protection of ecological environment and sustainable development are also illustrated in this article.
Individual Saccharomyces cerevisiae (S. cerevisiae) cells are coated with a uniform calcium mineral layer by first self-assembly of functional polymers (layer-by-layer technique, LbL) and then in situ mineralization under physiological conditions. The viability of the cells is maintained after the encapsulation. The enclosed cells become inert (stationary phase) and their lifetime can be extended. Furthermore, the mineral shell protects the cell under harsh conditions. The encapsulated S. cerevisiae can even survive the attack of the lytic enzyme zymolyase. The shell can also be used as a scaffold for chemical and biological functionalization. For example, S. cerevisiae becomes magnetic by the incorporation of Fe3O34 nanoparticles in the mineral layer. The present work demonstrates that the artificial shell has a great potential in the storage, protection, delivery, and modification of living cells. Furthermore, insights from systems biology combined with an understanding of the molecular mechanisms of functional shells will facilitate the tailoring of "super cells" through biomimetic mineralization.
Different from unicellular organisms and fertilized egg cells, cells inside human tissues are not separate but connected together by extracellular matrix (ECM). The ECM provides a physiological microenvironment for cells and regulates intercellular communication and a cell's dynamic behavior. Based on two over-expressed factors in the tumor microenvironment, matrix metalloproteinases (MMPs) and transferrin (TRF) receptors on the cell surfaces, we develop an enzyme-responsive locally injectable hydrogel system that target the tumor microenvironment. The cell-responsive hydrogel system is designed to release the encapsulated transferrin-drug conjugate in presence of MMPs secreted by cancer cells. The released conjugate is selectively targeted to tumor cells via receptor-mediated endocytosis by TRF receptors that are over-expressed in cancer cell, reducing nonspecific cytotoxicity to the normal cells. The injectable hydrogel drug-delivery system is minimally invasive, offering a highly tunable and programmable platform to modulate drug release through MMP crosslinker peptide sensitivity or tumor stage dependent MMP enzyme expression.
引文
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