Lactoferrin-Modified Ultra-Sustained Release Propofol Nanoparticles for Multi-Pathway Therapy of Depression via Intraperitoneal Injection.
6 affiliations
- 1Department of Psychiatry and Center for Brain Science, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.
- 2Yan'an Medical College of Yan'an University, Yan'an, Shaanxi, People's Republic of China.
- 3Clinical Medical College, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, People's Republic of China.
- 4Center for Translational Medicine, The First Affiliated Hospital of Xi' an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.
- 5College of Forensic Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.
- 6Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.
Abstract
Background
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.Methods
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.Results
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.Conclusion
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.
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BibTeX
@article{wu2026lactoferrinmodified,
title = {{Lactoferrin-Modified Ultra-Sustained Release Propofol Nanoparticles for Multi-Pathway Therapy of Depression via Intraperitoneal Injection.}},
author = {Zhenyi Wu and Junze Deng and Shunlian Li and Lu Yu and Hang Zhang and Yufeng Xun and Jing Bian and Jing Liu and Jianbo Zhang and Pu Lei and Qingyan Ma and Yajuan Fan and Zai Yang and Feng Zhu and Xiancang Ma and Daocheng Wu and Shuo Zhang},
journal = {International journal of nanomedicine},
year = {2026},
month = oct,
doi = {10.2147/ijn.s645818},
url = {https://europepmc.org/article/MED/42898626},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Lactoferrin-Modified Ultra-Sustained Release Propofol Nanoparticles for Multi-Pathway Therapy of Depression via Intraperitoneal Injection.
AU - Zhenyi Wu
AU - Junze Deng
AU - Shunlian Li
AU - Lu Yu
AU - Hang Zhang
AU - Yufeng Xun
AU - Jing Bian
AU - Jing Liu
AU - Jianbo Zhang
AU - Pu Lei
AU - Qingyan Ma
AU - Yajuan Fan
AU - Zai Yang
AU - Feng Zhu
AU - Xiancang Ma
AU - Daocheng Wu
AU - Shuo Zhang
PY - 2026
DA - 2026/10/14
JO - International journal of nanomedicine
DO - 10.2147/ijn.s645818
UR - https://europepmc.org/article/MED/42898626
AB - Background 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.Methods 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.Results 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.Conclusion 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.
SN - 1176-9114
SN - 1178-2013
ER -