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A Biomimetic Nanoplatform Alleviates Depression via GRP75-Targeted Mitochondria-Associated Endoplasmic Reticulum
Wenfei Wang1, Pengxiang Zhang1, Ye Peng1
1State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medical, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Abstract:
Dysfunction of microglial mitochondria-associated endoplasmic reticulum membranes (MAMs) and excessive oxidative stress are emerging pathological features of depression. Here, we developed P/F-Rg1@M, a macrophage-biomimetic nanomedicine designed to restore microglial homeostasis. This nanoplatform utilizes polydopamine (PDA) as a multifunctional carrier shell, which not only enables efficient loading of ginsenoside Rg1 through π-π stacking and hydrogen bonding, but also confers ROS/H2O2-responsive drug release behavior. The core consists of ROS-scavenging Fe3O4 nanozyme, and the entire nanoparticle is encapsulated within a macrophage membrane for targeted delivery to activated microglia. Mechanistically, P/F-Rg1@M exerts a synergistic therapeutic effect. Rg1 binding to GRP75 disrupts the IP3R-GRP75-VDAC1 complex, normalizing MAMs structural contacts, attenuating ER-to-mitochondrial calcium flux, and suppressing mitochondrial ROS production. Concurrently, the Fe3O4 core utilizes its nanozyme activity to clear residual ROS. In mice subjected to chronic social defeat stress (CSDS), P/F-Rg1@M effectively alleviated depressive-like behaviors, including social avoidance and anhedonia. transmission electron microscopy and electrophysiology confirmed that the nanomedicine structurally restored MAMs distance and reactivated the suppressed firing rates and gamma oscillations in hippocampal neurons. Notably, these therapeutic benefits were abolished in microglia-specific Hspa9 (GRP75) knockout mice. This study provides a nanotherapeutic approach that integrates structural organelle remodeling with microenvironmental regulation for psychiatric disorders.
Insights
Researchers developed a novel nanomedicine, P/F-Rg1@M, to combat depression by restoring microglial function and reducing oxidative stress. This targeted therapy effectively alleviated depressive behaviors in mice by repairing cellular structures and neuronal activity.
Area of Science:
- Neuroscience
- Biomedical Engineering
- Pharmacology
Background:
- Depression is linked to microglial mitochondria-associated endoplasmic reticulum membrane (MAM) dysfunction and oxidative stress.
- Microglial dysfunction plays a critical role in the pathophysiology of depression.
Purpose of the Study:
- To develop a macrophage-biomimetic nanomedicine (P/F-Rg1@M) for targeted delivery to microglia to restore homeostasis and treat depression.
- To investigate the therapeutic potential of P/F-Rg1@M in a mouse model of depression.
Main Methods:
- P/F-Rg1@M nanoplatform utilizes polydopamine (PDA) for ginsenoside Rg1 loading and ROS/H2O2-responsive release.
- Fe3O4 nanozyme core scavenges ROS, and macrophage membrane ensures targeted delivery to activated microglia.
- Evaluated therapeutic effects in mice subjected to chronic social defeat stress (CSDS), assessing depressive behaviors, MAMs structure, and neuronal activity.
Main Results:
- P/F-Rg1@M treatment significantly alleviated depressive-like behaviors in CSDS mice, including social avoidance and anhedonia.
- Nanomedicine restored MAMs structural integrity and reactivated neuronal firing rates and gamma oscillations in the hippocampus.
- Therapeutic benefits were dependent on microglia-specific Hspa9 (GRP75), confirming the mechanism of action.
Conclusions:
- P/F-Rg1@M offers a synergistic therapeutic approach by remodeling organelle structure and regulating the microenvironment.
- This nanotherapeutic strategy holds promise for treating psychiatric disorders by targeting microglial dysfunction and oxidative stress.
