近日，浙江大学田良飞团队报道了细胞工程中基于可编程肽的复杂凝聚微环境。该项研究成果发表在2025年11月26日出版的《美国化学会志》上。

肽类凝聚体因其序列可编程性、动态自组装能力及优异生物相容性，在生物医药和材料科学等交叉领域展现出显著潜力。尽管对相行为的理解已取得进展，但其高电荷密度和复杂的分子间相互作用仍给精确调控微环境和生物功能带来重大挑战。

研究组采用十肽序列（十精氨酸R10、十赖氨酸K10、十天冬氨酸D10），探索在D10中用苯丙氨酸（F）替代天冬氨酸（D），或在K10中用精氨酸（R）替代赖氨酸（K）对凝聚体微环境的影响。在R10/D10体系中，D到F的替换使热力学机制从低F%时的焓驱动相分离转变为高F%时的熵驱动相分离，增强了相分离倾向和盐耐受性，同时降低了内部极性和分子流动性。

K10/D10体系中R%的变化虽在R%≥20%时能稳定液滴，但对微滴黏度和极性的影响远小于F%的调控。两种替换均未改变生物大分子的富集能力，但D到F的替换破坏了双链DNA的二级结构。细胞共培养实验表明，R10/(FD)5和R10/D10复合凝聚体微滴均能快速黏附细胞膜，但R10/D10表现出更强的增殖抑制作用。该分子层面的分析为连接肽序列、凝聚体微环境与生物功能奠定了基础。

附：英文原文

Title: Programmable Peptide-Based Complex Coacervate Microenvironments for Cellular Engineering

Author: Chengying Yin, Cheng Wu, Xinran Yu, Jie Liu, Lantian Ma, Yifeng Zhu, Liangfei Tian

Issue&Volume: November 26, 2025

Abstract: Peptide-based coacervates demonstrate remarkable potential across interdisciplinary fields of biomedicine and materials science due to their sequence programmability, dynamic self-assembly capability, and exceptional biocompatibility. Despite progress in understanding their phase behavior, the high charge density and complex intermolecular interactions present significant challenges in precisely tailoring their microenvironments and biological functions. In this study, we utilized decapeptide sequences (decaarginine R10, decalysine K10, and decaaspartic acid D10) to explore the impact of substituting aspartic acid (D) with phenylalanine (F) in D10 or lysine (K) with arginine (R) in K10 on the microenvironment of coacervates. The replacement of D with F in the R10/D10 system led to a thermodynamic shift from enthalpy-driven (low F%) to entropy-driven (high F%) phase separation and enhanced phase separation propensity and salt resistance, while reducing internal polarity and molecular mobility. Varying R% in K10/D10 systems demonstrated limited impact on microdroplet viscosity and polarity compared to F% modulation, despite stabilizing droplets at R% ≥ 20%. Neither the D-to-F nor K-to-R substitutions altered the enrichment of biological macromolecules; however, the D-to-F substitution disrupted the secondary structure of double-stranded DNA. Cell coculture experiments confirmed that both R10/(FD)5 and R10/D10 complex coacervate microdroplets adhered to cell membranes rapidly, but R10/D10 exhibited stronger proliferation inhibition. This molecular-level analysis establishes a foundation for connecting the peptide sequence, condensate microenvironments, and biological functions.

DOI: 10.1021/jacs.5c09050

Source: https://pubs.acs.org/doi/abs/10.1021/jacs.5c09050