Duan Guangfei, Bai Xun, Pei Pengfei, Chen Long, Guo Yunhua, Li Feng, Xue Song, Luo Shi-Zhong
State Key Laboratory of Green Biomanufacturing, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China.
Department of chemical biology, College of Chemistry, Beijing University of Chemical Technology, Beijing 100029, China.
JACS Au. 2025 May 24;5(6):2567-2579. doi: 10.1021/jacsau.5c00197. eCollection 2025 Jun 23.
Phase-separated coacervates play a pivotal role in living cells by compartmentalizing and concentrating biomolecules, thereby facilitating the precise spatiotemporal regulation of biochemical processes. Inspired by biological systems, the burgeoning potential of phase separation in biomolecule delivery for therapeutic applications has garnered significant attention. Nonetheless, the precise phase separation of exogenous molecules in vivo presents a formidable challenge. In this study, we introduce a phase separation system, termed the Phase Separation Enhanced Drug Delivery System (PEDS), which operates at the cell membrane interface in vivo for targeted anticancer drug delivery. As a proof of concept, we demonstrate that an anticancer drug-conjugated peptide can undergo in situ co-phase separation with a designer targeting peptide on the cancer cell membrane. This in situ co-phase separation engenders a recruitment and enrichment effect, significantly enhancing the cellular internalization of the drug-conjugated peptide and thereby augmenting therapeutic efficacy. Notably, PEDS facilitates selective accumulation at tumor sites, with minimal drug deposition observed in organs, such as the liver and kidneys. This stands in stark contrast to conventional nanomedicines, which often suffer from nonspecific accumulation in the liver due to the necessity of ex situ drug preloading. Our findings underscore the potential of phase separation as a robust tool for in vivo therapeutic applications, offering new insights into its utility in targeted drug delivery systems.
相分离凝聚物通过对生物分子进行区室化和浓缩，在活细胞中发挥关键作用，从而促进生化过程的精确时空调控。受生物系统启发，相分离在生物分子递送治疗应用中的新兴潜力已引起广泛关注。然而，外源分子在体内的精确相分离面临巨大挑战。在本研究中，我们引入了一种相分离系统，称为相分离增强药物递送系统（PEDS），它在体内细胞膜界面发挥作用，用于靶向抗癌药物递送。作为概念验证，我们证明抗癌药物偶联肽可与癌细胞膜上的设计靶向肽原位共相分离。这种原位共相分离产生招募和富集效应，显著增强药物偶联肽的细胞内化，从而提高治疗效果。值得注意的是，PEDS促进在肿瘤部位的选择性积累，在肝脏和肾脏等器官中观察到的药物沉积极少。这与传统纳米药物形成鲜明对比，传统纳米药物由于需要异位药物预加载，常常在肝脏中出现非特异性积累。我们的研究结果强调了相分离作为体内治疗应用强大工具的潜力，为其在靶向药物递送系统中的应用提供了新见解。
