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

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/H 2 O 2 ‐responsive drug release behavior. The core consists of ROS‐scavenging Fe 3 O 4 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 Fe 3 O 4 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.