Delivery of Peptide Coacervates to Form Stable Interaction Hubs In Cells

Abstract

Cells contain membrane-bound and membraneless organelles that operate as spatially distinct biochemical niches. However, these reaction centers lose fidelity due to aging or disease. A grand challenge for biomedicine is restoring or augmenting cellular functionalities. Although commonly tackled by gene replacement therapy, an exciting new strategy is the delivery of protein-based materials that directly interact with and alter intracellular pathways. In this study, we sought to develop long-lasting materials capable of cellular uptake, akin to artificial organelles or synthetic interaction hubs. We show efficient delivery of micron-size peptide-based compartments into a variety of cell types. By loading coacervates with nanobodies and bioPROTACs, we demonstrate successful native target sequestration, and hub bioreactor function to selectively degrade targets inside human cells. These results represent an important step toward the development of synthetic organelles that can be fabricated in vitro and taken up by cells for applications in cell engineering and regenerative medicine.