A recent study from the University of Barcelona has unveiled a crucial molecular mechanism that enhances understanding of how cells communicate through extracellular vesicles (EVs). These small particles show significant therapeutic potential due to their role in transferring proteins, lipids, and nucleic acids between cells. The findings, published on November 28, 2025, in the Journal of Extracellular Vesicles, highlight the function of the Commander protein complex, previously associated with membrane recycling, in regulating the entry and destination of these vesicles within cells.
The research team was led by Professor Albert Lu from the Faculty of Medicine and Health Sciences at the University of Barcelona, alongside María Yáñez-Mó from the Severo Ochoa Center for Molecular Biology. Carles Enrich, also a professor at the same faculty, contributed to the study. According to Lu, “Understanding how receptor cells capture and process extracellular vesicles is essential to understanding how our body communicates at the molecular level.” He emphasized the importance of this knowledge for harnessing the therapeutic and diagnostic potential of EVs, noting that their effectiveness relies on directing them to the appropriate target cells.
Innovative Methodology for Discovery
To uncover the molecular mechanisms directing vesicle uptake, researchers employed an innovative approach using CRISPR-Cas9 technology. This method enables scientists to deactivate each of the over 20,000 human genes individually. By genetically modifying cells to deactivate specific genes, the team exposed these cells to EVs labeled with a fluorescent dye. Through flow cytometry, they measured the uptake of vesicles and utilized fluorescence-activated cell sorting (FACS) to isolate cells with varying capacities for vesicle capture. The deactivated genes in each group were identified using mass sequencing.
“This systematic and unbiased approach allows us to discover new regulators without relying on prior hypotheses,” explained Lu. The results indicated that the Commander endosomal recycling complex, composed of various proteins, acts as a fundamental regulator of vesicle uptake. The universality of this mechanism, confirmed through experiments with different human cell lines, suggests that its activity may vary based on cell type or physiological context.
Implications for Therapeutic Development
The implications of understanding this cellular communication process are substantial, particularly for therapeutic applications. The ability of EVs to traverse membranes and reach specific tissues positions them as natural vehicles for drug and therapeutic molecule transport. Lu stated, “Understanding how their entry, intracellular trafficking, and delivery of their molecular cargo are regulated opens the door to designing EVs with controlled directionality, improving their efficacy in regenerative, oncological or anti-inflammatory therapies.”
Currently, researchers are focused on gaining deeper insights into the Commander complex’s role in controlling the uptake and fate of EVs. They also aim to explore whether this mechanism is consistent across other cell types or tissues. Additionally, the team is investigating whether alterations in the Commander complex could impact cell communication in pathological contexts such as cancer or neurodegenerative disorders.
In conclusion, the long-term goal of this research is to manipulate the pathways governing cell communication, thereby enhancing the therapeutic and diagnostic utility of extracellular vesicles. The potential to improve EV efficacy could lead to significant advancements in medical treatments for various conditions, fundamentally transforming approaches to healthcare.
