Drug Molecule Recruitment Empowered by Phase Separation on Cell Membranes <i>In Vivo</i>

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.