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Abstract

Microglia modulation is a promising yet underexplored therapeutic target for traumatic brain injury (TBI). While mesenchymal stem cell (MSCs)-derived apoptotic bodies naturally regulate microglia and promote neural repair, their therapeutic potential remains largely untapped. In this study, we present an engineered apoptotic body-based platform (ALP) that facilitates immunometabolic modulation of microglia, offering a novel targeted treatment strategy for TBI. To construct ALP, we integrated MSCs-derived apoptotic body protein with natural biological product gastrodin-loaded liposomes. ALP has the ability to target inflammatory microglia and cross the blood-brain barrier. In vivo experiments analyses demonstrated that ALP not only reduces neuroinflammation but also restores cognitive and motor function in TBI mice. Besides, leveraging RNA sequencing, we uncovered a dual mechanism that ALP suppresses the NF-κB pathway while modulating the glucose metabolism pattern, providing the first systems-level insight into how apoptotic bodies improve TBI treatment. Our findings redefine engineered apoptotic bodies as programmable immunometabolic modulators, opening avenues for precision medicine in brain injury.