Extracellular vesicle surface proteins in tissue recognition, organotropism, biomarkers, and therapeutic engineering

Extracellular vesicles (EVs), including exosomes, carry donor-cell-derived molecular features that influence their interactions with recipient cells. This review links EV biogenesis and the assembly of surface recognition cues to cellular interactions, tissue distribution, and translational applications, with an emphasis on the evidence required to interpret surface localization, biomarker value, and therapeutic outcomes. These cues can contribute to cellular docking, uptake, and receptor signaling and, together with vesicle origin, physicochemical properties, administration route, vascular accessibility, protein corona formation, and clearance, help determine tissue distribution in disease. We discuss how EV-mediated communication participates in immune activation and suppression, anti-tumor cytotoxicity, pre-metastatic niche formation, metastatic progression, epithelial-mesenchymal transition, invasion, and immune evasion. We then summarize the translational potential of EV-associated surface signatures as candidate liquid-biopsy biomarkers for disease detection, staging, prognosis, and treatment monitoring. Surface engineering has been explored in preclinical models, where tissue accumulation, cellular uptake, functional cargo delivery, and therapeutic efficacy are distinct outcomes; modulation of pathogenic EV-cell interactions offers another potential therapeutic avenue. Progress toward clinical application will require standardized isolation and characterization, resolution of EV heterogeneity at the single-vesicle level, reproducible biodistribution and pharmacology, scalable manufacturing, and rigorous evaluation of safety and efficacy. Defining how surface-associated features operate within this multifactorial system may clarify disease mechanisms and guide the development of more precise EV-based diagnostics and therapies.