Targeting mitochondrial quality control in osteoarthritis with GrpE-like 1-loaded synovial mesenchymal stromal/stem cell small extracellular vesicles

Figure 1 Bench-to-bedside framework for intra-articular extracellular vesicles. A: Chemistry, manufacturing, and controls & characterization: Isolation workflow → identity/purity panels (tetraspanins/negative markers) → batch release (particles, μg) per Minimal Information for Studies of Extracellular Vesicles 2023; B: Dose & exposure: Normalized dose (particles and protein) and harmonized exposure/retention time-points (e.g., 1 hour, 24 hours, 7 days); C: Early clinical readouts: Endpoints mapped to the Outcome Measures in Rheumatology-Osteoarthritis Research Society International core domain set, with magnetic resonance imaging cartilage thickness as an exploratory structural biomarker informed by the Foundation for the National Institutes of Health Osteoarthritis Biomarkers Consortium; D: Transparency & oversight: Transparent Reporting and Centralizing Knowledge in Extracellular Vesicle Research/EV-METRIC badge and regulatory caution that no exosome products are United States Food and Drug Administration-approved; safety monitoring loop aligned with Investigational New Drug processes. CMC: Chemistry, manufacturing, and controls; NTA: Nanoparticle tracking analysis; MISEV2023: Minimal Information for Studies of Extracellular Vesicles (2023 update); ROI: Region of interest; OMERACT: Outcome Measures in Rheumatology; OARSI: Osteoarthritis Research Society International; WOMAC: Western Ontario and McMaster Universities Osteoarthritis Index; KOOS: Knee injury and Osteoarthritis Outcome Score; MRI: Magnetic resonance imaging; EV-TRACK: Transparent Reporting and Centralizing Knowledge in Extracellular Vesicle Research; EV-METRIC: Transparent Reporting and Centralizing Knowledge in Extracellular Vesicle Research Reporting Completeness Score; AEs: Adverse events; IND: Investigational New Drug; FDA: Food and Drug Administration.