Avicenna Research Institute Avicenna Journal of Medical Biotechnology 2008-2835 18 3 2026 07 01 Engineered Extracellular Vesicles for Cartilage Regeneration: Bridging Biological Complexity to Clinical Precision 189 206 250409 10.18502/ajmb.v18i3.22236 EN Shayan Boozarjomehri Amnieh Medical Biotechnology Research Center, AJA University of Medical Sciences, Tehran, Iran. 0009-0009-7916-617X Sina Mahmoudian Cancer Epidemiology Research Center (AJA-CERTC), AJA University of Medical Sciences, Tehran, Iran. 0009-0002-4993-7286 Mahdi Ghorbani Cancer Epidemiology Research Center, AJA University of Medical Sciences, Tehran, Iran. Javad Behroozi Cancer Epidemiology Research Center, AJA University of Medical Sciences, Tehran, Iran. Ali Shakerimoghaddam Infectious Diseases Research Center, AJA University of Medical Sciences, Tehran, Iran. Seyyed Morteza Tabatabaei Trauma and Surgery Research Center, AJA University of Medical Sciences, Tehran, Iran. Zahra Hami Toxicology Research Center, AJA University of Medical Sciences, Tehran, Iran. Mohsen Chamanara Toxicology Research Center, AJA University of Medical Sciences, Tehran, Iran. Reza Heydari Infectious Diseases Research Center AJA University of Medical Sciences, Tehran, Iran 0000-0003-2985-8396 Journal Article 2025 12 05 Osteoarthritis (OA) is a common degenerative joint disease characterized by pain, stiffness, progressive cartilage loss, and reduced mobility. Current treatments primarily aim to relieve symptoms rather than restore damaged cartilage, and durable regeneration of native hyaline cartilage remains a major clinical challenge. Extracellular Vesicles (EVs), particularly those derived from Mesenchymal Stem Cells (MSCs), have emerged as promising cell-free therapeutic platforms because of their ability to modulate inflammation, regulate chondrocyte activity, and influence extracellular matrix metabolism. However, EV heterogeneity, source-dependent variability, limited targeting efficiency, inconsistent cargo loading, and lack of standardized manufacturing protocols continue to restrict their clinical translation. This review summarizes recent advances in engineered EV-based strategies for OA and cartilage repair, including parental-cell preconditioning, genetic modification, surface functionalization, cargo loading, artificial EV platforms, and biomaterial-assisted delivery. Importantly, we distinguish between <em>in vitro</em> findings, preclinical animal studies, and early clinical evidence to provide a balanced assessment of translational readiness. We also discuss key regulatory and safety challenges, including GMP-compliant production, batch-to-batch variability, quality-control criteria, potency assays, scalability, biodistribution, and long-term safety. By integrating EV engineering with translational and regulatory perspectives, this review highlights the potential of engineered EVs as future disease-modifying tools for OA while emphasizing that their clinical efficacy and capacity to restore durable hyaline cartilage remain to be demonstrated in robust human studies https://www.ajmb.org/article_250409_a678ab2284b44f03a568f3d11bb77dc4.pdf