Abstract:

Cell surface receptors are important membrane proteins that play a crucial role in mediating signal transduction between the intra- and extracellular environments, which sense extracellular chemical or physical stimuli through their extracellular structures to transmit and amplify signals into the cell through their transmembrane domains, ultimately leading to cellular decision-making. Cell surface receptor clustering is a key molecular mechanism for precisely recognizing extracellular signals and initiating internal signaling cascade responses. The clustering and activation of cell surface receptors are essential for various biological processes such as cell migration, proliferation, apoptosis, and differentiation. In addition, mutations in membrane receptors can lead to the abnormal activation of intracellular signaling pathways, contributing to the pathogenesis of various diseases, such as cancer, diabetes, and atherosclerosis. Given the close relevance of receptor-mediated cellular functions to health and disease, researchers have devoted great effort to exploring the biophysical principles of receptor signal transduction and activation, as well as developing diverse molecular engineering strategies for manipulating receptor activation and the corresponding cellular function. With the emergence and rapid development of chemical synthetic biology, molecular engineering tools have been developed, making the rational regulation of receptor activation much simpler as well as more precise and diverse. This review first summarizes the key functional modules involved in regulating receptor clustering, including molecular recognition, spatial organization, dynamics, and cell-selective modules. We then highlight the latest research advances in highly controllable functional modules enabling the artificial engineering of receptor clusters with dynamic aggregation, specific responsiveness, temporal and spatial resolution, and high cell selectivity. Moreover, we emphasize the emerging applications of various precise molecular strategies for artificially controlling receptor clustering to manipulate cellular phenotypes and cell fates, including immune activation and in vivo tissue regeneration. Finally, we perspective the unresolved issues and challenges in developing receptor clustering strategies, pertaining to the mechanisms of receptor clustering, designs of molecular recognition modules, limitations of clinical applications, safety and long-term in vivo uses, and the potential applications of these strategies in disease treatment.

Key words: chemical synthetic biology, receptor clustering, component engineering, biomedical engineering, cell regulation

摘要：

细胞表面受体的聚集和激活在多种生物过程中发挥着重要作用，如细胞迁移、增殖、凋亡和分化。鉴于受体介导的细胞功能对健康和疾病的广泛相关性，研究人员一直致力于探究细胞受体信号传递和激活的生物化学和生物物理学机制，进而在其基础上开发多样的分子工程策略操纵受体信号和细胞功能。随着化学合成生物学的快速发展，一系列分子工程工具被开发出来用于理性控制受体，使得人工受体激活更加简单、精准和多样化。本综述首先总结了涉及调节受体聚集控制的关键功能元件，包括分子识别、空间组织、动态和细胞选择性元件。随后介绍了这些高度可控的功能模块在动态聚集、特定响应性、时空分辨和高细胞选择性的精准控制受体聚集分子工具的最新研究进展。此外强调了多种人工控制受体聚集的精准激活策略在细胞表型和命运操纵、免疫激活和活体组织修复方面的新兴应用。最后，本文从作用机理、元件工程、临床局限性、体内长效性等多个角度概述人工受体聚集策略当前面临的挑战和缺点。同时，本文也对其在疾病治疗领域的潜在应用进行了前瞻性的展望。

关键词: 化学合成生物学, 受体聚集, 元件工程, 生物医学工程, 细胞调控