Extracellular vesicles as the next-generation modulators of pharmacokinetics and pharmacodynamics of medications and their potential as adjuvant therapeutics.

BACKGROUND AND MAIN BODY: Pharmacokinetics (PK) and pharmacodynamics (PD) are central concepts to guide the dosage and administration of drug therapies and are essential to consider for both healthcare professionals and researchers in therapeutic planning and drug discovery. PK/PD properties of a drug significantly influence variability in response to treatment, including therapeutic failure or excessive medication-related harm. Furthermore, suboptimal PK properties constitute a significant barrier to further development for some candidate treatments in drug discovery. This article describes how extracellular vesicles (EVs) affect different aspects of PK and PD of medications and their potential to modulate PK and PD properties to address problematic PK/PD profiles of drugs. We reviewed EVs' intrinsic effects on cell behaviours and medication responses. We also described how surface and cargo modifications can enhance EV functionalities and enable them as adjuvants to optimise the PK/PD profile of conventional medications. Furthermore, we demonstrated that various bioengineering strategies can be used to modify the properties of EVs, hence enhancing their potential to modulate PK and PD profile of medications. CONCLUSION: This review uncovers the critical role of EVs in PK and PD modulation and motivates further research and the development of assays to unfold EVs' full potential in solving PK and PD-related problems. However, while we have shown that EVs play a vital role in modulating PK and PD properties of medications, we postulated that it is essential to define the context of use when designing and utilising EVs in pharmaceutical and medical applications. HIGHLIGHTS: Existing solutions for pharmacokinetics and pharmacodynamics modulation are limited. Extracellular vesicles can optimise pharmacokinetics as a drug delivery vehicle. Biogenesis and administration of extracellular vesicles can signal cell response. The pharmaceutical potential of extracellular vesicles can be enhanced by surface and cargo bioengineering. When using extracellular vesicles as modulators of pharmacokinetics and pharmacodynamics, the 'context of use' must be considered.

Extracellular vesicles transport RNA between cells: Unraveling their dual role in diagnostics and therapeutics.

Modern methods of molecular diagnostics and therapy have revolutionized the field of medicine in recent years by providing more precise and effective tools for detecting and treating diseases. This progress includes a growing exploration of the body's secreted vesicles, known as extracellular vesicles (EVs), for both diagnostic and therapeutic purposes. EVs are a heterogeneous population of lipid bilayer vesicles secreted by almost every cell type studied so far. They are detected in body fluids and conditioned culture media from living cells. EVs play a crucial role in communication between cells and organs, both locally and over long distances. They are recognized for their ability to transport endogenous RNA and proteins between cells, including messenger RNA (mRNA), microRNA (miRNA), misfolded neurodegenerative proteins, and several other biomolecules. This review explores the dual utilization of EVs, serving not only for diagnostic purposes but also as a platform for delivering therapeutic molecules to cells and tissues. Through an exploration of their composition, biogenesis, and selective cargo packaging, we elucidate the intricate mechanisms behind RNA transport between cells via EVs, highlighting their potential use for both diagnostic and therapeutic applications. Finally, it addresses challenges and outlines prospective directions for the clinical utilization of EVs.

Extracellular vesicles originating from melanoma cells promote dysregulation in haematopoiesis as a component of cancer immunoediting.

Haematopoiesis dysregulation with the presence of immature myeloid and erythroid immunosuppressive cells are key characteristics of the immune escape phase of tumour development. Here, the role of in vitro generated B16F10 tumour cell-derived extracellular vesicles (tEVs) as indirect cellular communicators, participating in tumour-induced dysregulation of haematopoiesis, was explored. The isolated tEVs displayed features of small EVs with a size range of 100-200 nm, expressed the common EV markers CD63, CD9, and Alix, and had a spherical shape with a lipid bilayer membrane. Proteomic profiling revealed significant levels of angiogenic factors, particularly vascular endothelial growth factor (VEGF), osteopontin, and tissue factor, associated with the tEVs. Systemic administration of these tEVs in syngeneic mice induced splenomegaly and disrupted haematopoiesis, leading to extramedullary haematopoiesis, expansion of splenic immature erythroid progenitors, reduced bone marrow cellularity, medullary expansion of granulocytic myeloid suppressor cells, and the development of anaemia. These effects closely mirrored those observed in tumour-bearing mice and were not seen after heat inactivating the tEVs. In vitro studies demonstrated that tEVs independently induced the expansion of bone marrow granulocytic myeloid suppressor cells and B cells while reducing the frequency of cells in the erythropoietic lineage. These effects of tEVs were significantly abrogated by the blockade of VEGF or heat inactivation. Our findings underscore the important role of tEVs in dysregulating haematopoiesis during the immune escape phase of cancer immunoediting, suggesting their potential as targets for addressing immune evasion and reinstating normal hematopoietic processes.

Antibody-displaying extracellular vesicles for targeted cancer therapy.

Extracellular vesicles (EVs) function as natural delivery vectors and mediators of biological signals across tissues. Here, by leveraging these functionalities, we show that EVs decorated with an antibody-binding moiety specific for the fragment crystallizable (Fc) domain can be used as a modular delivery system for targeted cancer therapy. The Fc-EVs can be decorated with different types of immunoglobulin G antibody and thus be targeted to virtually any tissue of interest. Following optimization of the engineered EVs by screening Fc-binding and EV-sorting moieties, we show the targeting of EVs to cancer cells displaying the human epidermal receptor 2 or the programmed-death ligand 1, as well as lower tumour burden and extended survival of mice with subcutaneous melanoma tumours when systemically injected with EVs displaying an antibody for the programmed-death ligand 1 and loaded with the chemotherapeutic doxorubicin. EVs with Fc-binding domains may be adapted to display other Fc-fused proteins, bispecific antibodies and antibody-drug conjugates.