Immunoglobulin-Directed Phase Separation for Cell-Specific Modulation of Receptor Signaling

Liquid-liquid phase separation is a fundamental process in cellular biology, influencing various cellular functions. Recent research highlights the critical role of phase separation in membrane-associated signaling complexes, where it spatiotemporally modulates signaling pathways. In this research, we have engineered a phase-separation system utilizing specific antibody-peptide multivalent interaction. In particular, the phase-separation system was constituted by a mutant Fc fragment from the human IgG1 and a peptide specifically bound to the mutant Fc. Further, by tethering the phase separation scaffolds to nanobodies targeting specific cell-surface receptors CXCR4 and DR5, we could specifically activate DR5 signaling in CXCR4⁺ cells. Moreover, the CXCR4/DR5-targeting phase separation system efficiently induced tumor cell apoptosis and tumor growth inhibition in the xenograft model, offering a novel strategy for tumor-specific apoptosis induction. This work demonstrates the potential of the immunoglobulin-directed phase separation systems as a tool for cell-specific signaling modulation for scientific research and therapeutic applications.