Phage as a Genetically Modifiable Supramacromolecule in Chemistry, Materials and Medicine.
Phage as a Genetically Modifiable Supramacromolecule in Chemistry, Materials and Medicine.
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DOI：
10.1021/acs.accounts.5b00557
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发表时间：
2016-06-21
影响因子：
18.3
通讯作者：
Mao C
中科院分区：
文献类型：
--
作者：
Cao B;Yang M;Mao C
丝状噬菌体是一种可遗传修饰的超大分子。它可以被描绘成一个半柔性的外壳（长约900 nm，宽约8 nm），由DNA核心和蛋白质外壳组成，前者在遗传上编码后者。虽然噬菌体生物工程和噬菌体展示技术在20世纪90年代之前就已经发展起来，但直到最近，这些技术才从超分子化学的角度广泛应用于化学、材料和生物医学研究。凭借我们在通过工程噬菌体DNA在其表面展示外源肽方面的专业知识，我们采用噬菌体来识别靶向特异性肽，构建新型有机-无机纳米杂化物，开发用于疾病治疗的生物材料，并产生用于疾病诊断的生物分析方法。与传统的仿生化学相比，基于噬菌体的超分子化学代表了化学、材料科学和医学的新前沿。本文介绍了近年来我们在噬菌体超分子化学领域的研究成果，将噬菌体独特的纳米纤维状结构和强大的肽展示技术结合到化学、材料科学和医学领域：（1）利用噬菌体模板成功地合成和组装了二氧化硅、羟基磷灰石和金纳米粒子，形成了新型功能材料;（2）将偶氮单元化学引入噬菌体上，以通过芳香族氨基与噬菌体表面上遗传展示的酪氨酸残基之间的重氮化反应形成光响应功能性偶氮噬菌体纳米纤维;（3）将噬菌体组装成2D膜，用于研究生物化学和生物活性的影响。（噬菌体上展示的肽序列）和生物物理（噬菌体膜的形貌）提示间充质干细胞（MSC）和诱导多能干细胞（iPSC）的增殖和分化（4）发现噬菌体可以诱导血管生成和成骨，用于基于MSC的血管化骨再生;（5）鉴定了新的乳腺癌细胞靶向肽和MSC靶向肽，并将它们分别用于显著提高靶向癌症治疗和基于MSC的基因递送的效率;（6）采用工程化噬菌体作为探针，实现对来自人类患者血清的生物标志物的超灵敏检测，用于疾病诊断;和（7）构建厘米级3D多层噬菌体组装体，其具有作为骨再生和功能性装置制造的支架的潜在应用。我们的研究结果表明，噬菌体确实是一种非常强大的超大分子，不仅适用于开发新型纳米结构和生物材料，而且还适用于推进生物医学的重要领域，包括分子靶向，癌症诊断和治疗，药物和基因递送，干细胞命运方向和组织再生。我们在化学、材料和医学方面利用噬菌体的成功表明，噬菌体本身在细胞水平上是无毒的，可以安全地用于体外检测生物标志物。此外，虽然我们已经证明了成功的体内组织再生诱导的噬菌体，我们相信未来的研究需要评估在体内的生物分布和潜在的风险的噬菌体为基础的生物材料。
Filamentous bacteriophage (phage) is a genetically modifiable supramacromolecule. It can be pictured as a semiflexible nanofiber (~900 nm long and ~8 nm wide) made of a DNA core and a protein shell with the former genetically encoding the latter. Although phage bioengineering and phage display techniques were developed before the 1990s, these techniques have not been widely used for chemistry, materials, and biomedical research from the perspective of supramolecular chemistry until recently. Powered by our expertise in displaying a foreign peptide on its surface through engineering phage DNA, we have employed phage to identify target-specific peptides, construct novel organic–inorganic nanohybrids, develop biomaterials for disease treatment, and generate bioanalytical methods for disease diagnosis. Compared with conventional biomimetic chemistry, phage-based supramolecular chemistry represents a new frontier in chemistry, materials science, and medicine. In this Account, we introduce our recent successful efforts in phage-based supramolecular chemistry, by integrating the unique nanofiber-like phage structure and powerful peptide display techniques into the fields of chemistry, materials science, and medicine: (1) successfully synthesized and assembled silica, hydroxyapatite, and gold nanoparticles using phage templates to form novel functional materials; (2) chemically introduced azo units onto the phage to form photoresponsive functional azo-phage nanofibers via a diazotization reaction between aromatic amino groups and the tyrosine residues genetically displayed on phage surfaces; (3) assembled phage into 2D films for studying the effects of both biochemical (the peptide sequences displayed on the phages) and biophysical (the topographies of the phage films) cues on the proliferation and differentiation of mesenchymal stem cells (MSCs) and induced pluripotent stem cells (iPSCs) and identified peptides and topographies that can induce their osteogenic differentiation; (4) discovered that phage could induce angiogenesis and osteogenesis for MSC-based vascularized bone regeneration; (5) identified novel breast cancer cell-targeting and MSC-targeting peptides and used them to significantly improve the efficiency of targeted cancer therapy and MSC-based gene delivery, respectively; (6) employed engineered phage as a probe to achieve ultrasensitive detection of biomarkers from serum of human patients for disease diagnosis; and (7) constructed centimeter-scale 3D multilayered phage assemblies with the potential application as scaffolds for bone regeneration and functional device fabrication. Our findings demonstrated that phage is indeed a very powerful supramacromolecule suitable for not only developing novel nanostructures and biomaterials but also advancing important fields in biomedicine, including molecular targeting, cancer diagnosis and treatment, drug and gene delivery, stem cell fate direction, and tissue regeneration. Our successes in exploiting phage in chemistry, materials, and medicine suggest that phage itself is nontoxic at the cell level and can be safely used for detecting biomarkers in vitro. Moreover, although we have demonstrated successful in vivo tissue regeneration induced by phage, we believe future studies are needed to evaluate the in vivo biodistribution and potential risks of the phage-based biomaterials.