Researchers at Karolinska Institutet have developed a technique that enables efficient delivery of therapeutic proteins and RNA to cells. The method, presented in Nature Communications, shows promising results in animal studies to deliver gene editors and protein therapeutics.
The method is based on so-called extracellular vesicles (EVs), tiny bubbles that are naturally secreted by cells and can transport biologically active molecules between cells. Researchers have now succeeded in improving these bubbles by introducing two key components: a small part of a bacterial protein called intein and a so-called fusogenic protein from a virus.
The fusogenic protein helps the bubbles to fuse with the endosomal membrane and release their contents into the cell, while the intein can cut itself and thus help release therapeutic proteins inside the cell.
"This innovative engineering strategy represents a major step forward for extracellular vesicle technology, effectively overcoming key barriers such as poor endosomal escape and limited intracellular release," says Professor Samir EL Andaloussi , last author of the study and researcher at the Department of Laboratory Medicine . "Our in vivo findings highlight the potential of engineered EVs as a versatile platform for delivering therapeutics to treat a broad range of conditions, including systemic inflammation, genetic diseases, and neurological disorders."
Expanding on this, the study's first author, Dr. Xiuming Liang at the Department of Laboratory Medicine , adds: "By improving the efficiency and reliability of therapeutic delivery into target cells, this technology could significantly broaden the application of advanced medicines."
Brain changes in mice
In experiments on cells and live animals, the researchers were able to efficiently deliver Cre recombinase, a protein that can cut and paste DNA, and Cas9/sgRNA complexes, which are used to edit genes. When extracellular vesicles loaded with Cre recombinase were injected into the brains of mice, a significant change in cells in the hippocampus and cortex brain structures was observed.
"This gives hope to use the CRISPR/Cas9 gene scissors or similar tools to treat severe genetic diseases of the central nervous system, such as Huntington's disease and spinal muscular atrophy," says Xiuming Liang.
The researchers also demonstrated that the technique could be used to treat systemic inflammation in mice.
The study was performed within the Karolinska ATMP Center. Joint corresponding authors on the study are Xiuming Liang, Joel Nordin and Samir EL Andaloussi
See the scientific article for information on funding and potential conflicts of interest.
Publication
Liang X, Gupta D, Xie J, Van Wonterghem E, Van Hoecke L, Hean J, Niu Z, Ghaeidamini M, Wiklander OPB, Zheng W, Wiklander RJ, He R, Mamand DR, Bost J, Zhou G, Zhou H, Roudi S, Estupiñán HY, Rädler J, Zickler AM, Görgens A, Hou VWQ, Slovak R, Hagey DW, de Jong OG, Uy AG, Zong Y, Mäger I, Perez CM, Roberts TC, Carter D, Vader P, Esbjörner EK, de Fougerolles A, Wood MJA, Vandenbroucke RE, Nordin JZ, El Andaloussi S
Nat Commun 2025 Apr;16(1):4028
