Extracellular vesicle therapeutics for cardiac regeneration: Overcoming standardization hurdles

Figure 1 Combination of exercise and mesenchymal stem cell-derived extracellular vesicles contributes to attenuated cardiac hypertrophy via dual pathway modulation. ↑: Increased expression/activation; ↓: Decreased expression/inhibition; ★: Fine-tuned regulation; Color code: Blue - exercise; green - EVs; purple – synergy. MSC-EVs: Mesenchymal stem cell-derived extracellular vesicles; IL-6: Interleukin-6; TNF-α: Tumor necrosis factor-α; GSH: Glutathione; EV: Extracellular vesicle; ERK: Extracellular signal-regulated kinase; Akt: Protein kinase B; mTOR: Mammalian target of rapamycin; SERCA2a: Sarcoplasmic/endoplasmic reticulum calcium ATPase 2a; MMP-9: Matrix metalloproteinase 9; ECM: Extracellular matrix; CHP: Cell-penetrating peptide; CEP: Cell-entering peptide; ROS: Reactive oxygen species.

Figure 2 Standardized workflow and key decision points for clinical-grade extracellular vesicles in cardiac repair (depicts the four core components of clinical-grade extracellular vesicle therapy. Upstream cellular programming and production; rigorous characterization and quality control to define critical quality attributes; preclinical efficacy prediction and patient stratification for cohort selection; clinical translation with real-time monitoring and comprehensive safety evaluation to ensure effective treatment). EVs: Extracellular vesicles; SEC: Size exclusion chromatography; TFF: Tangential flow filtration; miRNA: MicroRNA; ITGA4: Integrin subunit alpha 4; CQAs: Critical Quality Attributes; hiPSC-CMs: Human induced pluripotent stem cell-derived cardiomyocytes; IL-6: Interleukin-6; sST2: Soluble suppression of tumorigenicity-2; PET: Positron emission tomography; NIRF: Near-infrared fluorescence.