Topic: An EV Translational Path from Clinic to Lab to Clinic?

Despite major advances in extracellular vesicle (EV) biology, the clinical translation of EV-based therapies remains limited. A key challenge is the disconnect between preclinical models and the complex, dynamic nature of human disease. Bridging this gap requires a critical reassessment of the tools and strategies used to study EVs - ensuring they are better aligned with real-world clinical challenges and patient-specific contexts.

This Special Issue directly addresses this translational barrier. Building on themes from the international workshop “From the Clinical Problem to the Research Model” (held at IRCCS Ospedale Galeazzi - Sant'Ambrogio in October 2025), the issue is grounded in the belief that successful translation begins in the clinic. Instead of fitting clinical questions into existing research frameworks, this approach reverses the paradigm - starting with actual patient needs to guide the development of models, technologies, and strategies that more accurately reflect clinical complexity and therapeutic relevance.

Topics include:

● Development and application of new approach methodologies (NAMs)for disease modeling and therapeutic evaluation of EVs;

● Integration of in silico models, digital twins, andAI-driven tools to simulate EV behavior, dosing, and biodistribution;

● Use of EV-based assays as mechanistic probesor functional readouts in regenerative medicine, oncology, inflammation, and degenerative diseases;

● Strategies for standardizing EV isolation, characterization, and potency testing;

● Approaches to accelerate clinical translationthrough scalable manufacturing, reproducibility, and clinically relevant delivery models.

This collection presents a forward-looking perspective in which EVs serve not only as therapeutic agents or biomarkers, but also as key components in the development of next-generation, patient-informed, and clinically actionable research models. By bringing together clinicians, model developers, and translational scientists, this Special Issue fosters a research ecosystem rooted in clinical reality and oriented toward impactful innovation.