Lactoferrin-Modified Ultra-Sustained Release Propofol Nanoparticles for Multi-Pathway Therapy of Depression via...

Depression imposes a significant burden on global public health, and traditional antidepressants are limited by slow onset, low efficacy, and high recurrence rates. Intraperitoneal injection of propofol can rapidly exert anti-anhedonic effects by regulating the VTA-NAc dopaminergic and GABAergic signaling pathways. However, its application in depression treatment is limited by rapid systemic clearance, poor brain permeability, and significant systemic toxicity. Moreover, the simple lipophilic structure of propofol and the limited drug-loading and long-term controlled-release performance of conventional physically encapsulated nanocarriers hinder the development of long-acting propofol formulations.

Lactoferrin-functionalized PVA-propofol nanoparticles (LF-PVA@Pro NPs) were prepared based on the strong intermolecular affinity between PVA and propofol, as validated by molecular dynamics simulations. Their physicochemical properties, in vitro release behavior, brain-targeting efficiency, biosafety, and in vivo antidepressant efficacy were systematically characterized using CRS-induced depressive mouse models through multiple behavioral and histological assessments.

LF-PVA@Pro NPs achieved a drug loading of 19.3% and exhibited sustained in vitro release for 100 h. Following intraperitoneal injection, the formulation maintained therapeutic brain concentrations for 100 h (6-8-fold longer than free propofol) and increased cerebral drug accumulation by 2.5-fold. Its LD50 was 2802 mg/kg, 2.36-fold higher than that of free propofol, ensuring safety at the therapeutic dose of 40 mg/kg. In vivo studies demonstrated that LF-PVA@Pro NPs markedly alleviated depressive- and anxiety-like phenotypes, reduced VTA/NAc neuronal injury, and restored c-Fos, GABA, and DAT expression, thereby reactivating reward circuits.

LF-modified ultra-sustained brain-targeted nanoparticles enable multi-pathway long-term depression intervention, offering a translatable strategy to repurpose propofol as a rapid-onset antidepressant for chronic stress-related depression.