Peptide-Propofol Prodrug with Self-Assembly and Triggered Release for Antidepressant Therapy.

Major depressive disorder (MDD) remains difficult to treat with agents that are simultaneously rapid, durable, and well-tolerated. Propofol shows fast antidepressant-like actions but is limited by anesthetic liability, a short half-life, and poor brain-selective exposure. Here, we report Nap-FFYK(propofol), a peptide-propofol self-assembling prodrug engineered to decouple anesthetic burden from sustained antidepressant benefit. Physicochemical characterization confirmed the stimulus-triggered conversion of Nap-FFYK(propofol) to Nap-FFYK and propofol. The prodrug displays high drug loading, robust self-assembly into nanospheres, and carboxylesterase (CES)-responsive release, enabling on-site liberation of propofol with a lower risk of respiratory depression. In the chronic social defeat stress mouse model, a single administration produced rapid and durable antidepressant-like effects with a swift recovery from transient sedation. Mechanistic analyses demonstrated reduced microglial activation, restored astrocytic support, preserved blood-brain barrier integrity, and enhanced synaptic plasticity in hippocampal circuits. These findings validate a targeting-assembly release strategy for propofol repurposing and establish peptide self-assembly prodrugs as a tractable platform for brain-directed, rapid-acting antidepressant therapy. This approach provides a blueprint to pair hour-scale symptom relief with improved safety and durability, addressing key limitations of existing rapid-acting interventions.