Department of Chemistry, Brandeis University, 415 South Street, Waltham, Massachusetts 02453, United States.
Acc Chem Res. 2023 Nov 7;56(21):3076-3088. doi: 10.1021/acs.accounts.3c00542. Epub 2023 Oct 26.
Higher-order or supramolecular protein assemblies, usually regulated by enzymatic reactions, are ubiquitous and essential for cellular functions. This evolutionary fact has provided a rigorous scientific foundation, as well as an inspiring blueprint, for exploring supramolecular assemblies of man-made molecules that are responsive to biological cues as a novel class of therapeutics for biomedicine. Among the emerging man-made supramolecular structures, peptide assemblies, formed by enzyme reactions or other stimuli, have received most of the research attention and advanced most rapidly.In this Account, we will review works that apply enzyme-instructed self-assembly (EISA) to generate intracellular peptide assemblies for developing a new kind of biomedicine, especially in the field of novel cancer nanomedicines and modulating cell morphogenesis. As a versatile and cell-compatible approach, EISA can generate nondiffusive peptide assemblies locally; thus, it provides a unique approach to target subcellular organelles with exceptional cell selectivity. We have arranged this Account in the following way: after introducing the concept, simplicity, and uniqueness of EISA, we discuss the EISA-formed intracellular peptide assemblies, including artificial filaments, in the cell cytosol. Then, we describe the representative examples targeting subcellular organelles, such as mitochondria, endoplasmic reticulum, Golgi apparatus, lysosomes, and the nucleus, by enzyme-instructed intracellular peptide assemblies for potential cancer therapeutics. After that, we highlight the recent exploration of the transcytosis of peptide assemblies for controlling cell morphogenesis. Finally, we provide a brief outlook of enzyme-instructed intracellular peptide assemblies. This Account aims to illustrate the promise of EISA-generated intracellular peptide assemblies in understanding diseases, controlling cell behaviors, and developing new therapeutics from a class of less explored molecular entities, which are substrates of enzymes and become building blocks of self-assembly after the enzymatic reactions.
高等或超分子蛋白质组装体，通常受酶反应调控，普遍存在且对细胞功能至关重要。这一进化事实为探索对生物信号有响应的人工分子超分子组装体提供了严格的科学基础和富有启发性的蓝图，这类组装体有望成为生物医学领域的新型治疗药物。在新兴的人工超分子结构中，由酶反应或其他刺激诱导形成的肽组装体受到了最多的研究关注，并取得了最快的进展。本综述将回顾应用酶指导的自组装（EISA）生成用于开发新型生物医学的细胞内肽组装体的相关工作，尤其是在新型癌症纳米药物和调节细胞形态发生领域。作为一种多功能且与细胞兼容的方法，EISA 可以在局部生成非扩散的肽组装体，从而为靶向具有特殊细胞选择性的亚细胞细胞器提供了独特的方法。我们按照以下方式组织了这篇综述：在介绍 EISA 的概念、简单性和独特性之后，我们讨论了在细胞细胞质中形成的 EISA 细胞内肽组装体，包括人工丝。然后，我们描述了通过酶指导的细胞内肽组装体靶向亚细胞细胞器（如线粒体、内质网、高尔基体、溶酶体和细胞核）的代表性实例，用于潜在的癌症治疗。之后，我们强调了最近对肽组装体跨细胞转运的探索，以控制细胞形态发生。最后，我们对酶指导的细胞内肽组装体进行了简要展望。本综述旨在说明 EISA 生成的细胞内肽组装体在理解疾病、控制细胞行为以及开发新的治疗药物方面的潜力，这些药物是酶的底物，并且在酶反应后成为自组装的构建块。
