bims-evecad 2025-10-05 papers

Issue of 2025–10–05
five papers selected by
Cliff Dominy

Curr Gene Ther. 2025 09 30.

Precision Medicine: Design of Immune Inert Exosomes for Targeted Gene Delivery.

Exosomes represent the smallest size among extracellular vesicles, which also include apoptotic bodies and microvesicles. Exosomes are natural nanocarriers that play a key role in intracellular communication, consisting of a hydrophobic lipid bilayer membrane and a hydrophilic core. The membrane compositions of exosomes are similar to those of the parent cells from which they are generated. Normally, the exosome membrane contains diacylglycerol, ceramide, cholesterol, and various surface proteins, including tetraspanins and Lamb2. Almost all cell types secrete exosomes into body fluids through exocytosis, including stem cells, epithelial cells, endothelial cells, immune cells, tumor cells, neurons, mast cells, oligodendrocytes, reticulocytes, macrophages, platelets, and astrocytes. Every cell type expresses a distinct type of exosomes carrying various bioactive molecules. Exosomes are major transporters of bioactive cargo, including enzymes, receptors, growth and transcription factors, nucleic acids, lipids, and other metabolites, which strongly affect the physiology of recipient cells. Exosomes are not only potent drug and gene delivery nanocarriers, but also have potential for disease diagnosis, tissue regeneration, and immunomodulation. Exosomes are present in various body fluids, including plasma, serum, saliva, milk, nasal secretions, urine, amniotic fluid, semen, and cerebrospinal fluid, among others. Stem cell-made exosomes are potential natural therapeutics, which is due to their rejuvenating cargo and ability to cross biological barriers. However, natural exosomes' inefficient cargo transfer and short lifespan in the bloodstream have hindered their progress in therapeutic interventions. Genetic engineering of the parent cell allows for loading specific therapeutic cargo into the lumen of newly generated exosomes and/or displaying certain homing peptides or ligands at their surface, leading to extension of their lifespan and precise delivery to specific organs or tissues. This minireview explores the creation of designer exosomes through parent cell engineering and their utilization for guiding the delivery of tailored therapeutic cargo to specific organs while evading the host's innate immune response.

Keywords: Designer exosomes; extracellular vesicles; invisible exosomes; smart exosomes.; tailored cargos

DOI: https://doi.org/10.2174/0115665232409032250908114520

J Extracell Vesicles. 2025 Oct;14(10): e70172

Lipoprotein Association Fluorometry (LAF) as a Semi-Quantitative Characterization Tool to Assess Extracellular Vesicle-Lipoprotein Binding.

Raluca Ghebosu, Jenifer Pendiuk Goncalves, Nur Indah Fitri, Dalila Iannotta, Mohammad Farouq Sharifpour, Elaina Coleborn, Alex Loukas, Fernando Souza-Fonseca-Guimaraes, Joy Wolfram.

Extracellular vesicles (EVs) are biological nanoparticles that play important roles in (patho)physiological processes and are promising new therapeutic and diagnostic tools. Recent evidence suggests that other circulating biological nanoparticles, primarily lipoproteins, bind to EVs, changing their biological identity. Such binding has been demonstrated with complex qualitative techniques, such as cryogenic transmission electron microscopy. There is a need to rapidly and simply quantify EV-lipoprotein binding, as such complexes could have major implications for EV biology and medical applications. This study developed lipoprotein association fluorometry (LAF; based on fluorescent lipophilic indocarbocyanine dyes), as a first-of-its-kind, simple and quick assay to assess EV binding to lipoproteins. The LAF assay was validated with synthetic nanoparticles, small molecules, polymers and proteins that display known interactions with lipoproteins. The LAF assay demonstrates that EVs from various human and non-human (nematode and bacteria) sources bind to very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL). Notably, EVs derived from cancerous cells displayed substantially increased binding to VLDL, LDL and plasma compared to EVs from normal cells. Additionally, the LAF assay revealed that EVs from metastatic cancer cells bound to VLDL to a greater extent than those from corresponding patient-matched non-metastatic cancer cells. On the contrary, EVs displayed minimal binding to high-density lipoprotein (HDL). Taken together, the LAF assay is capable of measuring EV-lipoprotein binding in a simple, rapid and semi-quantitative manner, leading to new opportunities to probe EV biology and develop novel therapeutics, and diagnostics.

Keywords: LDL; VLDL; bad cholesterol; corona; exosomes; microvesicles

DOI: https://doi.org/10.1002/jev2.70172

Exp Mol Med. 2025 Oct 01.

Cardiac repair and regeneration: cell therapy, in vivo reprogramming, and the promise of extracellular vesicles.

R M Imtiaz Karim Rony, Joshua D Tompkins.

Therapeutic interventions to replenish lost cardiomyocytes and recover myocardium functions following ischemic myocardial infarction (MI) remain major goals in the cardiac regeneration field. Clinical trials harnessing autologous or allogeneic cell therapy approaches from both cardiac and noncardiac cells sources, thus far, demonstrate marginal improvement. Moreover, complications such as arrythmias and graft rejections associated with cellular or organ-based therapies continue to prevail. Extracellular vesicles, on the other hand, are cell-derived, nano-sized, cargo-containing biomolecules that have emerged as potent alternatives to cell-based cardiac regeneration/replacement therapy. Recent studies demonstrate that most stem-cell-derived extracellular vesicles (Stem-EVs) are nonimmunogenic and carry cardioprotective therapeutic cargos. Moreover, administration of multiple Stem-EV types in animal models of acute MI results in reduced inflammation, apoptosis, smaller infarct size and improved cardiac functionality. With recent developments, engineered Stem-EVs with enhanced cardiac targeting, prolonged circulation and recombinant therapeutic cargos may tilt the cardiac regeneration field toward these novel cell-free biologics. Here we provide a brief overview of current approaches to repair and replenish damaged cardiomyocytes following MI via cell therapy and in vivo reprogramming, and we delve deeply into the therapeutic potentials of Stem-EVs in cardiac repair and regeneration.

DOI: https://doi.org/10.1038/s12276-025-01549-3

Front Cardiovasc Med. 2025 ;12 1565104

Composition of cardiac-derived extracellular vesicles changes with vesicle origin and determines uptake.

Sruti Bheri, Jessica R Hoffman, Hyun-Ji Park, Swarnima Roychowdhury, Felipe Takaesu, Samuel G Moore, David A Gaul, Michael E Davis.

Introduction: Cardiovascular disease (CVD) is a leading cause of mortality worldwide. The potency of cell-based therapies for CVD is increasingly attributed to the release of small extracellular vesicles (sEVs) which consist of a lipid/protein membrane and encapsulate nucleic cargo. Specifically, sEVs from ckit + progenitor cells (CPCs) and mesenchymal stromal cells (MSCs) are shown to be pro-reparative, with clinical trials conducted. Despite copious research into sEV cargo, the role of parent cell type on sEV membrane composition and its effects on sEV uptake mechanism by recipient cells remain unclear. This is crucial for designing sEV-based therapeutics as uptake mechanism dictates the functionality of the cargo.
Methods: In this study we investigate the role of sEV parent cell and membrane composition on the mechanism of EV uptake by recipient cells.
Results: We find that sEV membrane lipid and protein composition varies by parent cell type. Further, vesicle uptake mechanism varies by both sEV parent cell type and recipient cell type, with clathrin-mediated uptake being the most variable across parent cell conditions. Using a partial least squares regression model, we observe that proteins important in clathrin-mediated uptake (e.g., TPM1, MRC2, FSTL1, LTBP1) are dissimilar to other vesicle uptake mechanisms.
Discussion: This work underscores the importance of the sEV source and membrane composition on uptake, and in turn the importance of selecting specific sEVs based on the target recipient cells for CVD therapies.

Keywords: bioinformatics; extracellular vesicles (EVs); lipidomics; proteomics; stem cell; uptake

DOI: https://doi.org/10.3389/fcvm.2025.1565104