Candida albicans Extracellular Vesicles Upregulate Nrg1 Transcription Repressor to Inhibit Self-Hyphal Development and Candidemia

<i>Candida albicans</i> is the most prevalent opportunistic pathogenic fungus in humans, and its extracellular vesicles (EVs) play crucial roles in its growth and pathogenesis. Previously, we found that <i>C. albicans</i> EVs at low levels could promote its growth. However, the effects of EVs when accumulated at high concentrations in <i>C. albicans</i> remain unclear. This study revealed that a high concentration of EVs inhibited hyphal development in <i>C. albicans</i> in a time-dependent manner. Transcriptome and RT-qPCR analyses showed that EVs significantly upregulated the transcription repressor <i>NRG1</i> and downregulated hyphal-specific genes in a laboratory strain and five clinical isolates, while EVs failed to repress <i>nrg1Δ/Δ</i> hyphae. Further experiments confirmed that EVs upregulated the upstream transcription factor <i>SKO1</i> (but downregulated <i>BRG1</i>) to increase <i>NRG1</i> expression, thereby inhibiting hyphal formation. Cargo proteins in EVs were key components that inhibited <i>C. albicans</i> hyphal growth. Additionally, EV-treated <i>C. albicans</i> showed improved mouse survival and reduced organ fungal burden in candidemia, but EVs did not attenuate virulence in <i>nrg1Δ/Δ</i>-infected mice. These results reveal that <i>C. albicans</i> EVs at high levels play an important role in its pathogenicity and highlight the potential for novel therapeutic strategies.