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

## TL;DR

A new intranasal treatment using plant-derived extracellular vesicles shows rapid antidepressant effects by targeting the brain and reducing inflammation.

## Contribution

A novel intranasal thermosensitive hydrogel delivers plant-derived extracellular vesicles to the brain, bypassing the blood-brain barrier for rapid antidepressant effects.

## Key findings

- Intranasal EVs@IN reduced depressive and anxiety-like behaviors in mouse models of depression.
- EVs suppressed neuroinflammation and oxidative stress while restoring hippocampal synaptic plasticity.
- EVs@IN demonstrated long-term biocompatibility and efficient brain-targeted delivery via olfactory pathways.

## 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.

A schematic illustration of Chlorella vulgaris‐derived extracellular vesicles (EVs) for brain‐targeted delivery and their antidepressant mechanisms. This diagram depicts how an intranasal thermosensitive hydrogel (EVs@IN) encapsulating Chlorella vulgaris‐derived EVs achieves rapid antidepressant effects by modulating astrocyte phenotypic transformation, reducing neurotoxic complement C3 release and suppressing neuroinflammation.