Exosome engineering for efficient intracellular delivery of soluble proteins using optically reversible protein–protein interaction module

TLDR

Nanoparticle‑mediated delivery of functional macromolecules is promising for treating various diseases, and cell‑derived exosomes have emerged as a new strategy for in vivo delivery of nucleotides and chemical drugs. The study introduces EXPLORs, a new tool for intracellular delivery of target proteins. EXPLORs load cargo proteins into exosomes by integrating a blue‑light‑controlled reversible protein–protein interaction module with exosome biogenesis. Protein‑loaded EXPLORs markedly increase intracellular cargo protein levels and function in recipient cells in vitro and in vivo, demonstrating their potential for efficient intracellular transfer of protein therapeutics.

Abstract

Abstract Nanoparticle-mediated delivery of functional macromolecules is a promising method for treating a variety of human diseases. Among nanoparticles, cell-derived exosomes have recently been highlighted as a new therapeutic strategy for the in vivo delivery of nucleotides and chemical drugs. Here we describe a new tool for intracellular delivery of target proteins, named ‘exosomes for protein loading via optically reversible protein–protein interactions’ (EXPLORs). By integrating a reversible protein–protein interaction module controlled by blue light with the endogenous process of exosome biogenesis, we are able to successfully load cargo proteins into newly generated exosomes. Treatment with protein-loaded EXPLORs is shown to significantly increase intracellular levels of cargo proteins and their function in recipient cells in vitro and in vivo . These results clearly indicate the potential of EXPLORs as a mechanism for the efficient intracellular transfer of protein-based therapeutics into recipient cells and tissues.