Nose‐to‐Brain Delivery of Chlorella vulgaris Extracellular Vesicles for Antidepressant Effects

ABSTRACT Current antidepressants face limitations due to the blood–brain barrier (BBB), systemic side effects and delayed onset. Here, we engineered an intranasal thermosensitive hydrogel (EVs@IN) encapsulating Chlorella vulgaris ‐derived extracellular vesicles (EVs) for sustained nose‐to‐brain delivery. EVs@IN significantly enhanced nasal mucosal retention and facilitated targeted transport of EVs to the hippocampus via olfactory pathways, while minimizing pulmonary exposure and clearance. In mouse models of depression (LPS‐induced and CUMS), intranasal EVs@IN elicited rapid and potent alleviation of depressive‐ and anxiety‐like behaviours. Mechanistically, EVs modulated astrocyte phenotypic transformation, reducing the release of neurotoxic complement C3 and suppressing neuroinflammation. Concurrently, they activated the Nrf2‐Pgc‐1α pathway, enhanced antioxidant defences (elevated SOD and GSH), mitigated oxidative stress and restored synaptic plasticity and neurogenesis in the hippocampus. Furthermore, we demonstrated the capacity of EVs to serve as efficient drug carriers for brain delivery. EVs@IN exhibited excellent long‐term biocompatibility in vivo. Our findings establish plant‐derived EVs within a sustained‐release intranasal platform as a promising, scalable and BBB‐bypassing strategy for the rapid treatment of depression and potentially other neuropsychiatric disorders.