Exosome-mediated immunomodulation of osteoarthritic synovitis: macrophage fibroblast crosstalk, targeted delivery, and clinical translation
Abstract
Osteoarthritis (OA) is a whole-joint disorder in which synovial inflammation plays an important role in pain, cartilage loss, fibrosis, and joint progression. Traditional systemic and intra-articular treatments offer relief, have a short duration of joint presence, lack complete cell targeting, and have side effects. Exosomes are membrane-enclosed extracellular vesicles that serve as vehicles to safeguard pharmacological cargo, mediate cellular uptake, and target the inflammatory tissues of the joints. This review discusses exosome-mediated targeted drug delivery to the synovial space for OA treatment, focusing on inflammatory mechanisms, carrier engineering, pharmacokinetics, therapeutic efficacy, safety, and clinical translation. Exosomes originating from mesenchymal stromal cells, chondrocytes, macrophages, and other cells can regulate synovial macrophages and fibroblast-like synoviocytes, inhibit the activation of cytokines and inflammasomes, inhibit the production of matrix-degrading enzymes, and protect the mitochondrial and autophagic functions of chondrocytes. Intra-articular persistence, small molecule loading, protein and regulatory nucleic acid loading, ligand display, and hydrogel-based retention may enhance potency. Most of this evidence is preclinical, and the reported benefits are limited by the lack of a uniform definition of vesicles, poorly standardized dosing, uncertain synovial specificity, limited pharmacokinetic data, and a lack of long-term safety evaluation. To develop a clinical product, scalable good manufacturing practices are needed, as well as assays for potency based on the mechanism of action, reproducible loading of the cargo, quantitative biodistribution, and controlled trials with patients with synovitis.
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BibTeX
@article{afzal2026exosomemediated,
title = {{Exosome-mediated immunomodulation of osteoarthritic synovitis: macrophage fibroblast crosstalk, targeted delivery, and clinical translation}},
author = {Muhammad Afzal and Mohd Masih Uzzaman Khan and Bader A. Alhazmi and Surya Nath Pandey and Arcot Rekha and Shweta Patel and Gaurav Gupta and Jyoti Maithani Kalra and Kapil Kalra and Chandan Kumar and Namrata Pundir and Md Sadique Hussain},
journal = {Frontiers in Immunology},
year = {2026},
month = nov,
doi = {10.3389/fimmu.2026.1975010},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1975010},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Exosome-mediated immunomodulation of osteoarthritic synovitis: macrophage fibroblast crosstalk, targeted delivery, and clinical translation
AU - Muhammad Afzal
AU - Mohd Masih Uzzaman Khan
AU - Bader A. Alhazmi
AU - Surya Nath Pandey
AU - Arcot Rekha
AU - Shweta Patel
AU - Gaurav Gupta
AU - Jyoti Maithani Kalra
AU - Kapil Kalra
AU - Chandan Kumar
AU - Namrata Pundir
AU - Md Sadique Hussain
PY - 2026
DA - 2026/11/09
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1975010
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1975010
AB - Osteoarthritis (OA) is a whole-joint disorder in which synovial inflammation plays an important role in pain, cartilage loss, fibrosis, and joint progression. Traditional systemic and intra-articular treatments offer relief, have a short duration of joint presence, lack complete cell targeting, and have side effects. Exosomes are membrane-enclosed extracellular vesicles that serve as vehicles to safeguard pharmacological cargo, mediate cellular uptake, and target the inflammatory tissues of the joints. This review discusses exosome-mediated targeted drug delivery to the synovial space for OA treatment, focusing on inflammatory mechanisms, carrier engineering, pharmacokinetics, therapeutic efficacy, safety, and clinical translation. Exosomes originating from mesenchymal stromal cells, chondrocytes, macrophages, and other cells can regulate synovial macrophages and fibroblast-like synoviocytes, inhibit the activation of cytokines and inflammasomes, inhibit the production of matrix-degrading enzymes, and protect the mitochondrial and autophagic functions of chondrocytes. Intra-articular persistence, small molecule loading, protein and regulatory nucleic acid loading, ligand display, and hydrogel-based retention may enhance potency. Most of this evidence is preclinical, and the reported benefits are limited by the lack of a uniform definition of vesicles, poorly standardized dosing, uncertain synovial specificity, limited pharmacokinetic data, and a lack of long-term safety evaluation. To develop a clinical product, scalable good manufacturing practices are needed, as well as assays for potency based on the mechanism of action, reproducible loading of the cargo, quantitative biodistribution, and controlled trials with patients with synovitis.
SN - 1664-3224
ER -