Extracellular vesicles (EVs) have emerged as promising vehicles for therapeutic delivery due to their natural role in intercellular communication and biocompatibility. Traditional methods often rely on fusing the therapeutic protein to a scaffold, which can compromise the protein's function and stability. The IDEA approach circumvents this issue by packaging and delivering native proteins without scaffolds, preserving their functionality. In vitro and in vivo experiments with cGAS-EVs demonstrated significant activation of interferon signaling and potent antitumor responses. The study further explores the immune mechanisms involved, including the remodeling of the tumor microenvironment and the role of neutrophils and T cells in mediating these effects.
Key findings from the study include:

1. Scaffold-Free Protein Delivery: The IDEA method effectively packages and delivers native proteins via EVs without the use of a scaffold. This preserves the protein's stability and functionality, making it a versatile platform for various therapeutic proteins. ng.
2. Activation of Immune Responses: cGAS-EVs were shown to activate interferon signaling pathways, leading to enhanced antitumor immunity. This was evidenced by significant remodeling of the tumor microenvironment, including increased infiltration of neutrophils and activation of T cells.
3. Synergistic Antitumor Effects: When combined with immune checkpoint inhibitors, cGAS-EVs produced a synergistic effect, further boosting antitumor efficacy. This suggests that IDEA could enhance the effectiveness of existing immunotherapies.
4. Single-Cell RNA Sequencing Insights: scRNA-seq analysis revealed that cGAS-EVs led to substantial changes in the tumor immune landscape, including increased expression of interferon response genes and activation markers in T cells. This provided insights into the specific immune cell populations and pathways involved in the antitumor response.

The study presents the IDEA platform as a groundbreaking approach for the intracellular delivery of therapeutic proteins using engineered EVs. By avoiding the use of scaffold proteins, IDEA maintains the integrity and functionality of the delivered proteins. The application of this method to deliver cGAS proteins resulted in robust activation of immune responses and significant antitumor effects. The synergistic enhancement of antitumor efficacy when combined with immune checkpoint inhibitors highlights the potential of IDEA to improve current cancer immunotherapies. This approach could be extended to other therapeutic proteins, including those involved in gene editing and other intracellular processes, marking a significant advancement in the field of protein-based therapeutics. The work entitled “ Engineered extracellular vesicles enable high-efficient delivery of intracellular therapeutic proteins ” was published on Protein & Cell (published on Mar. 22, 2024).
DOI: 10.1093/procel/pwae015