A Biomimetic Nanoplatform Alleviates Depression via GRP75-Targeted Mitochondria-Associated Endoplasmic Reticulum Membranes Disassembly and Nanozyme-Driven ROS Scavenging

22/08/2026

AI Summary

Macrophage-biomimetic nanoplatform P/F-Rg1@M combines PDA shell, Fe3O4 nanozyme core and Rg1 cargo for ROS-responsive, microglia-targeted delivery.
Rg1 binds GRP75 to disassemble IP3R-GRP75-VDAC1, normalise MAM contacts, reduce ER to mitochondrial calcium flux and mitochondrial ROS.
In CSDS mice P/F-Rg1@M rescues social avoidance, anhedonia, restores MAM ultrastructure and hippocampal firing; benefits lost in microglia-specific Hspa9 knockout.

AI Summary

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.

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.

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.

Basic summary

Adv Healthc Mater. 2026 Aug 21:e71628. doi: 10.1002/adhm.71628. Online ahead of print.

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.

PMID:42629983 | DOI:10.1002/adhm.71628

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