---
title: "Extracellular vesicle-based drug delivery in pediatric immune thrombocytopenia — limited source da"
id: "frontiers-in-immunology-10-extracellular-vesicle-based-drug-delivery-in-pediatric-immune-thrombocytopenia"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-10-extracellular-vesicle-based-drug-delivery-in-pediatric-immune-thrombocytopenia"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1951209"
published_at: "2026-10-23T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Extracellular vesicle-based drug delivery in pediatric immune thrombocytopenia — limited source da
## Provenance & Clinical Metadata
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- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1951209)
- **Published At:** 2026-10-23T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The source document accessible via the provided URL contains only site navigation and header information; the full article text was not present in the retrieved content. - The item is labeled as a REVIEW article in Frontiers in Immunology, and the page header includes the article title: “Extracellular vesicle-based drug delivery in pediatric immune thrombocytopenia.” - The retrieved file does not include the review’s abstract, methods, detailed findings, or references; no experimental data, clinical endpoints, or dosing information were available. - Because the JINA content lacks the manuscript body, no specific patient cohorts, sample sizes, timelines, or therapeutic regimens can be summarized from this source. - Key topics implied by the title—**Extracellular vesicle**, **immune thrombocytopenia**, and **pediatric** populations—are present only in the metadata; the source did not report mechanistic, translational, or clinical recommendations. - For editorial use, the absence of primary text prohibits extraction of outcomes, safety signals, or methodological quality indicators; the document should be re-queried at the publisher site for the full review before clinical citation or guideline consideration.
## Clinical Analysis & Structured Key Points
Frontiers | Extracellular vesicle-based drug delivery in pediatric immune thrombocytopenia REVIEW article Front. Immunol. , 23 October 2026 Sec. Autoinflammatory Disorders Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1951209 Published in Frontiers in Immunology Autoinflammatory Disorders 7 impact factor 11.3 citescore Part of a Research Topic Advanced nanotherapeutics and targeted drug delivery for autoimmune and autoinflammatory disorders Submission open 5704 views 3 articles Editor & Reviewers Edited by S M Syed Mahmood Reviewed by A P Anil Pareek L M Lisa M Minter Outline Figures and Tables Figure 1 View in article Figure 2 View in article Figure 3 View in article Figure 4 View in article Table 1 Overview of endogenous MSC-EVs cargo and their immunomodulatory mechanisms in pediatric autoimmune diseases. View in article Table 2 Comparative evaluation of therapeutic platforms for pediatric ITP, including PNPs, LNPs, MSC-EVs and MSC cell-therapy. View in article REVIEW article Front. Immunol. , 23 October 2026 Sec. Autoinflammatory Disorders Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1951209 Extracellular vesicle-based drug delivery in pediatric immune thrombocytopenia O D Oriana Di Domenico 1 M M Maria Maddalena Marrapodi 1 G D Giuseppe Di Feo 1 L A Lucia Argenziano 1 F R Francesca Rossi 1 * A D Alessandra Di Paola 1,2 1. Department of Woman, Child and General and Specialist Surgery, University of Campania “Luigi Vanvitelli”, Naples, Italy 2. Department of Life Sciences, Health and Health Professions, Link Campus University, Rome, Italy Article metrics View details Abstract Pediatric immune thrombocytopenia (ITP) is an acquired immune-mediated disorder triggered by autoantibody production directed against glycoproteins on the platelet surface, leading to platelet destruction in the spleen and impaired megakaryopoiesis in the bone marrow. The immune response is further compromised by a dysregulated inflammatory environment involving T-cell proliferation, pro-inflammatory macrophage polarization and defective immunomodulatory function of mesenchymal stromal cells (MSCs). Although first-line therapies such as intravenous immunoglobulin G and corticosteroids remain beneficial, they are also associated with relevant toxicities and do not fully address the systemic nature of the disease in pediatric patients. Extracellular vesicles (EVs) as cellular mediators secreted by all kinds of cells are currently under investigation as promising therapeutic nanocarriers. MSC-derived extracellular vesicles (MSC-EVs) in particular, have emerged as therapeutic candidates due to their low immunogenicity, high biocompatibility, and intrinsic ability to transport cargo capable of modulating the immune response. MSC-EVs may simultaneously regulate T-cell balance, influence macrophage polarization, support megakaryopoiesis, and deliver regulatory molecules to specific targets. Bioengineering strategies involving cargo loading and surface functionalization may further improve their therapeutic potential and homing capabilities. Although key barriers to clinical translation remain, MSC-EVs represent a promising platform for a precision and cell-free approach in pediatric ITP. Although direct pediatric-specific evidence remains limited, in this review we provide a comprehensive overview of the biological properties, immunomodulatory mechanisms, and translational challenges of MSC-EVs, comparing their advantages against conventional pharmacological approaches and other available synthetic nanocarriers. 1 Introduction Immune thrombocytopenia (ITP) is an acquired immune-mediated disorder and the most common cause of thrombocytopenia in pediatric patients ( 1 ). It is characterized by a platelet count of less than 100 × 10 9 /L occurring in children between the ages of 1 and 18 years, resulting from autoantibody-mediated platelet destruction and impaired platelet production ( 2 ). These autoantibodies are directed against platelet glycoproteins (GP) IIb/IIIa or GPIb/IX, which results in engaging of both adaptive and innate immunity mechanisms ( 3 ). The pathogenesis of ITP is multifaceted and involves the loss of immune tolerance to platelet and megakaryocyte antigens, expansion of autoreactive T and B lymphocytes, enhanced macrophage-mediated platelet phagocytosis, and suppressed megakaryopoiesis in the bone marrow, leading to a variety of clinical manifestations primarily involving coagulation deficits. Furthermore, dysregulation of the T helper (Th) 1/Th2 and Th17/regulatory T cell (Treg) balances contributes to the establishment of a pro-inflammatory environment that sustains autoimmune platelet destruction ( 4 ). Figure 1 summarizes the key factors leading to the pathogenesis of pediatric ITP. Figure 1 Schematic overview of the pathogenesis of pediatric ITP. The loss of immune tolerance leads to the escape of autoreactive T cells from thymic negative selection. These T cells, once in the periphery, provide help to autoreactive B cells specific for platelet glycoproteins GPIIb/IIIa and GPIb/IX, promoting their differentiation into antibody-secreting plasma cells. Resulting autoantibodies trigger peripheral platelet clearance via splenic macrophage phagocytosis and complement activation. Simultaneously, the autoimmune response is sustained through the production of pro-inflammatory cytokine, further exacerbating the T-cell subsets imbalance. Supporting and enhancing macrophage polarization toward an M1 pro-inflammatory phenotype and impairing megakaryopoiesis within the bone marrow niche. Schifferli et al. highlighted the issue of misdiagnosed thrombocytopenia in children and adolescents, underscoring the importance of accurate classification ( 5 ). Broadly, ITP is clustered by the length of the disease and is classified as newly diagnosed or persistent, within 3 months, or between 3 to 12 months from diagnosis respectively, and lastly as chronic when the disorder lasts for more than 12 months ( 6 ). All forms of ITP have overlapping pathophysiology and exhibit similar signs and clinical symptoms, nevertheless, classification and prior identification of the disease are fundamental to dictate the following treatments and how the disease should be clinically managed ( 7 ). Regarding clinical manifestations, they may vary widely depending on the patient and in particular, they range from asymptomatic or mild bruising and petechiae, to severe potentially life-threatening haemorrhages ( 8 ). ITP presents a good prognosis for pediatric patients, where more than 70% of cases experience spontaneous recovery within six months of diagnosis, but up to 30% develop chronic ITP ( 9 ). A higher risk of chronicity is observed as the age of onset or diagnosis increases, reaching a peak at around over 10 years ( 10 , 11 ). Overall, ITP as a disease significantly impacts the quality of life (QoL) of the patients, primarily due to restrictions in daily recreational and sports activities, resulting in social isolation. In recent years, increased attention to assessing the QoL of ITP patients has highlighted how thrombocytopenia negatively affects not only mood and state of mind, but also physical energy and cognitive performance (e.g. chronic fatigue syndrome) in a significant number of pediatric patients ( 12 ). Regarding treatment options for ITP, it is reserved in patients with severe symptoms, such as significant bleeding, therefore manifestations that impact the QoL of both the child and family. In fact, treatment decisions are based primarily on bleeding and clinical manifestation severity, not on the platelet count alone. As previously stated, the majority of ITP patients do not present any symptoms, therefore they do not require any pharmacologic treatment ( 13 ). According to the latest therapy plan proposed by the “Associazione Italiana Ematologia Oncologia Pediatrica” (AIEOP) committee in 2024, the first line of therapy involves the use of intravenous immunoglobulin G (IVIG) or high-dose corticosteroids, such as prednisone or intravenous methylprednisolone, administered orally or parenterally. Second-line agents are indicated for persistent or chronic ITP with significant bleeding, impaired QoL, or dependence on first-line treatments, and encompass the use of several different drugs ( 10 , 13 ). Thrombopoietin Receptor Agonists (TPO-RAs) like Eltrombopag, Avatrombopag and Romiplostim, are employed to stimulate platelet production and are administered orally ( 14 , 15 ). Among other second-line agents, immunosuppressive agents such as Mycophenolate Mofetil (MMF), and Sirolimus in refractory cases are also established options ( 16 – 18 ). In the case in which all previous therapy plans were not successful, Rituximab, a monoclonal antibody against CD20, a glycoprotein expressed on the surface of B cells leading to a reversible B-cell depletion, represents another important second-line option to implement ( 19 – 21 ). Regarding patients who do not present any symptoms, absence or mild bleedings, observation is mandatory. In contrast, severe bleeding, life threatening situations or refractory cases may require combined therapies involving IVIG together with corticosteroids or platelets transfusions. Splenectomy is considered only in exceptional circumstances in pediatric patients and is strongly limited to children >5 years of age, after failure of available medical therapies, in chronic disease and when QoL is substantially impaired ( 13 , 21 ). Despite the availability of a plethora of different therapeutic approaches based on the needs of the patients, all of them present several limitations and serious adverse effects. Specifically, common complications of first-line therapies include gastrointestinal and renal toxicity, weight gain, sleep and behavioral disturbances, increased susceptibility to infections, thrombosis, hypertension, and hyperglycemia, particularly following prolonged treatment ( 22 , 23 ). Understanding the nuances of this condition and emerging therapeutic strategies may help in improving patient outcomes, therefore major attention has been given to the developing of novel therapeutic approaches in treating such a clinical variable disease. These limitations have highlighted the need to search for novel therapeutic approaches that can address the multifaceted pathophysiology of ITP while lessening the overall side effects ( 9 ). In this context, extracellular vesicles (EVs) have emerged as promising biological nanocarriers with inherent immunomodulatory properties. EVs are particles delimited by a lipid bilayer membrane, variable in size ranging from nanometers to micrometers, that are released by all cell types and are incapable of self-replication ( 24 ). Nowadays, EVs are considered among the most promising candidates for therapeutic development, specifically due to some of their most prominent properties, such as low immunogenicity, biocompatibility, ability to cross biological membranes, therefore these abilities taken all together position them as versatile carriers for targeted drug delivery ( 25 ). The primary aim of this review is to summarize and encompass the current knowledge and focus attention on the promising and novel therapeutic opportunities revolving around the implementation of EVs as a potential drug-delivery and free-cell therapeutic option in pediatric ITP. While other reviews have already addressed the therapeutic potential of EVs in ITP as a generic immunomodulatory platform, their scope has predominantly been confined to the adult population or to a broad description of MSC-EV biology and their therapeutic mechanisms. The present review builds upon prior literature focusing explicitly on pediatric ITP, contextualizing EVs-based therapies within the age-specific epidemiology and the functional impairment of MSCs in ITP patients resulting in ineffective autologous cell-based approaches and answering the primary question of whether and how extracellular vesicles, and MSC-derived EVs in particular, could be developed and integrated as drug-delivery systems for the treatment of pediatric ITP. Moreover, it provides a side-by-side comparison of MSC-EVs with alternative nanocarrier platforms, including liposomes, lipid nanoparticles (LNPs), platelet membrane-coated nanoparticles (PNPs), and whole MSCs therapy, essential to delineate the actual translational niche that EVs may occupy. Lastly, it discusses EVs engineering and cargo-loading strategies, an area that remains largely unexplored in previous ITP-specific literature, but that will likely determine the clinical future advancement of this platform. 2 Extracellular vesicles: biology and classification Despite firstly being reported as merely a different way for disposing of debris and waste material in the cell, in recent years EVs have been the subject of much more scrutiny from the scientific community, gaining substantial interest for their promising and versatile implementation in various sectors ( 26 ). The first ever reported sighting and description of EVs was in 1946 by Chargaff and West observing particles derived from platelets in plasma, enhancing and promoting coagulation ( 27 ). EVs are secreted in various degrees by all kinds of cells, moreover, they are segregated in different subcategories based primarily on biogenesis, size, cargos and function. According to the “Minimal information for studies of extracellular vesicles” (MISEV) 2023 guidelines, it is advised against using a specific nomenclature depending on different biogenesis of EVs or size, such as microvesicles or exosomes, whereas the overall classification of vesicles is recommended to be into: extracellular vesicles, synthetic vesicles, and artificial cell-derived vesicles ( 24 ). Despite the discouragement to adopt such nomenclature, nowadays the employment of different EVs’ names is still commonly based on the previous division ( Figure 2 ). Nevertheless, following the MISEV2023 guidelines, in this review all types of vesicles will be collectively referred to as EVs. Figure 2 Historical classification and biogenesis of extracellular vesicles. EVs are traditionally divided into three subtypes based on biogenesis and size: exosomes (30–150 nm), originating from the endosomal pathway via multivesicular bodies (MVBs); microvesicles (50–1000 nm), generated by direct outward budding and shedding of the plasma membrane; and apoptotic bodies (1000–5000 nm), the largest subclass, formed through membrane blebbing during programmed cell death. This size-based classification, while widely used in literature and by the scientific community, it is not fully supported by current MISEV2023 guidelines which recommend the collective term extracellular vesicles due to the difficulty of isolation and classification. EVs harbor an array of bioactive molecules, which would otherwise be degraded in the extracellular environment, thereby exhibiting a protective role for these molecules, which include proteins, lipids, and nucleic acids such as RNA (microRNA, mRNA, etc.) originating from their parental cells. Furthermore, it is important to point out that even within the same cell type, EV populations are heterogeneous. For instance, mesenchymal stromal cells (MSCs) may release distinct EVs differing in cargo, surface markers or size depending on variables such as culture conditions or donor availability, which concur in one of the major limitations of using EVs: manufacturing reproducibility ( 28 ). EVs are well-known for their intrinsic stability, low immunogenicity, biocompatibility, extended half-life and enhanced ability to cross biological barriers (e.g. Blood Brain Barrier), reaching specific organs difficult to target by normal drugs or many synthetic particles. Furthermore, they physiologically already serve as mediators and carriers of several molecules whose role is pivotal in regulating intra and extracellular communication and might be bioengineered from parent cells, addressing the complex manufacturing challenges associated with the production of other delivery systems ( 29 ). Therefore, EVs play a fundamental role in physiological and pathological processes of the whole organism and may represent a novel cell-free therapeutic alternative, as drug and gene delivery systems, nutraceutical carriers, or biomarkers for liquid biopsies, disease diagnosis and prognosis ( 30 ). 2.1 Sources of EVs and their immunomodulatory functions Notably, EVs have been extensively studied as pivotal effectors in regulating the equilibrium of the immune system and how it responds and reacts to stimuli for future therapeutic application ( 31 ). Recent studies have demonstrated that EVs, based on the conditions and the kind of cell of origin, perform diverse and essential roles in immune system response ( 32 ). EVs exercise their pivotal function through two major ways: directly affecting the target immune cell to activate downstream signals, or indirectly by transporting microRNAs (miRNAs). However, EVs production and action in immune responses modulation is convoluted and is further aggravated as EVs also act as intercellular signals, thereby they are constantly generated by all immune cells and tissue resident cells, rendering it difficult to describe the overall microenvironment ( 33 ). In the context of different pathologies, EVs produced by B cells, T cells, Natural Killer (NK) cells, dendritic cells (DCs), macrophages, MSCs and neutrophils likely work in a coordinated fashion to provide positive and negative signals for inflammation, thus depending on the cell of origin, EVs may carry out different functions. Furthermore, surface ligands on EVs may be involved in regulating their uptake by specific target cells, further impacting immune response. EVs can transport cytokines to regulate other immune cells’ polarization and activity, and also, both MHCI- and MHCII-antigen complexes have been reported on EVs, which may be presented to T cells ( 34 – 36 ). Beyond the transfer of MHC-antigen complex between cells by EVs, the latter may also induce additional signals to immune cells by transferring intact receptors to the plasma membrane of target cells ( 34 ). In particular, EVs from DCs and from B cells directly stimulate T cell proliferation and cytokine production in vitro ( 37 ). DCs are fundamental not only for their primary function as antigen presenting cell (APC), but they have been reported to secrete EVs for antigen presentation and adaptive response. On the other hand, EVs derived from T cells are generally involved in antiviral and antitumoral activity, and their production and secretion is enhanced by stimulation of T cell receptor ( 38 , 39 ). Other fundamental cells in managing innate immunity and immune responses in general are macrophages which play various different functions depending on the polarization and stimulant molecules in the environment. EVs derived from macrophages may have an inhibitory or stimulatory effect on immune functions depending on the polarization of the producer macrophage and type of cargo ( 40 , 41 ). B cells are the source of anti-platelet autoantibodies, being the main drivers of ITP pathogenesis, therefore in ITP, B cell-derived EVs carry pathogenic cargo including autoantibody-loaded immune complexes and pro-inflammatory miRNAs that further amplify the humoral immune response against platelets ( 31 ). Understanding how EVs derived from different immune cell populations participate in immune regulation and dysregulation provides the framework for interpreting the pathogenic role of endogenous EVs in ITP and immune diseases in general, and the therapeutic potential of MSC-EVs discussed more in depth in the following sections. 2.2 MSC-derived EVs in ITP: mechanisms and therapeutic potential Among the various cellular sources of EVs, those isolated from MSCs are the most studied nowadays ( 42 ). MSCs are multipotent stem cells that have already
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