Exercise-responsive extracellular vesicles in Parkinson’s disease: A candidate interface between peripheral adaptation and central pathobiology

Parkinson’s disease (PD) is increasingly recognised as a multisystem neurodegenerative disorder that extends beyond nigrostriatal dopaminergic degeneration and striatal dopamine depletion to involve neurovascular dysfunction, chronic neuroinflammation, disrupted proteostasis, mitochondrial stress, and circuit-level maladaptation. Although exercise is one of the most promising non-pharmacological interventions for PD, the mechanisms underlying its clinical and functional benefits, as well as its potential neuroprotective effects, remain incompletely understood. This Review proposes that extracellular vesicles (EVs) may act as a candidate systems-level link between peripheral exercise adaptation and disease-relevant central nervous system processes. We explore the impact of exercise on EV release, cargo composition, cellular origin, and signaling potential, considering factors such as exercise type, intensity, duration, training status, age, and health conditions. We examine how exercise-responsive EVs may intersect with key PD-relevant mechanisms, including neurovascular unit integrity, microglial activation and inflammation resolution, astrocyte-neuron metabolic support, mitochondrial resilience, α-synuclein (α-syn) proteostasis, and striatal synaptic plasticity. Beyond mechanistic considerations, we evaluate the potential of EVs as indicators of disease status, progression, and exercise responsiveness, as well as their potential relevance to patient stratification and therapeutic development. We also address key unresolved issues such as methodological heterogeneity, limited source attribution, and a lack of causal evidence linking exercise-responsive EV populations to disease-relevant outcomes in PD. By placing EVs at the centre of the exercise–PD interface, this Review provides a testable framework to bridge exercise physiology and PD biology and identifies future research directions for evaluating biomarker-guided exercise strategies and vesicle-oriented treatments.