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Here, we developed P\/F\u2010Rg1@M, a macrophage\u2010biomimetic 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 \u03c0\u2013\u03c0 stacking and hydrogen bonding, but also confers ROS\/H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    \u2010responsive drug release behavior. The core consists of ROS\u2010scavenging Fe\n                    <jats:sub>3<\/jats:sub>\n                    O\n                    <jats:sub>4<\/jats:sub>\n                    nanozyme, and the entire nanoparticle is encapsulated within a macrophage membrane for targeted delivery to activated microglia. Mechanistically, P\/F\u2010Rg1@M exerts a synergistic therapeutic effect. Rg1 binding to GRP75 disrupts the IP3R\u2010GRP75\u2010VDAC1 complex, normalizing MAMs structural contacts, attenuating ER\u2010to\u2010mitochondrial calcium flux, and suppressing mitochondrial ROS production. Concurrently, the Fe\n                    <jats:sub>3<\/jats:sub>\n                    O\n                    <jats:sub>4<\/jats:sub>\n                    core utilizes its nanozyme activity to clear residual ROS. In mice subjected to chronic social defeat stress (CSDS), P\/F\u2010Rg1@M effectively alleviated depressive\u2010like 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\u2010specific\n                    <jats:italic>Hspa9<\/jats:italic>\n                    (GRP75) knockout mice. This study provides a nanotherapeutic approach that integrates structural organelle remodeling with microenvironmental regulation for psychiatric disorders.\n                  <\/jats:p>","DOI":"10.1002\/adhm.71628","type":"journal-article","created":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T05:35:41Z","timestamp":1787376941000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Biomimetic Nanoplatform Alleviates Depression via GRP75\u2010Targeted Mitochondria\u2010Associated Endoplasmic Reticulum Membranes Disassembly and Nanozyme\u2010Driven ROS Scavenging"],"prefix":"10.1002","volume":"15","author":[{"given":"Wenfei","family":"Wang","sequence":"first","affiliation":[{"name":"State 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 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