Fungal extracellular vesicles as biomarkers in candidiasis: biogenesis, virulence, and CNS diagnostic applications

Invasive candidiasis remains a life-threatening infection with mortality rates reaching 40-55%, yet current gold-standard diagnostics such as blood culture are often slow and insensitive. This review evaluates fungal extracellular vesicles (EVs) as both mechanistic drivers of pathogenesis and clinical utility as biomarkers. We first outline EV biogenesis and translocation across the fungal cell wall, emphasizing the roles of turgor pressure and enzymatic remodeling. We then discuss how EVs act as protected carriers of virulence factors, such as candidalysin and Als3, which modulate tissue invasion and host responses. While profiling these circulating fungal EVs provides a promising and sensitive window into systemic invasive candidiasis, this approach faces unique hurdles in cases of central nervous system (CNS) involvement. In the CNS, fungal signatures are sequestered behind the blood-brain barrier (BBB) and heavily diluted by the vast pool of peripheral EVs, rendering total plasma analysis inadequate. To overcome these barriers, we propose a specialized diagnostic framework that combines dual-marker immunocapture of neuron-derived EVs (NDEVs), using neural cell adhesion molecule (NCAM) and intercellular adhesion molecule 5 (ICAM-5), with the detection of internal Candida-associated cargo. We emphasize that while this host-vesicle enrichment strategy is mechanistically grounded, it requires standardized isolation workflows and prospective clinical validation before deployment as a non-invasive platform for early CNS diagnosis.