Mitochondrial‐Targeting DNA Origami Delivering TIPE‐2 mRNA for Microglial Metabolic Reprogramming and Neurological Recovery in Intracerebral Hemorrhage

Secondary brain injury after intracerebral hemorrhage (ICH) is driven by persistent neuroinflammation and metabolic dysfunction, in which aberrantly activated microglia form a self‐amplifying cycle that impairs neural repair. TIPE‐2 (TNFAIP8‐like 2) is a key immunometabolic regulator, but its therapeutic application in the central nervous system (CNS) is limited by poor mRNA stability and inefficient intracellular targeting. This study innovatively constructs a triphenylphosphonium (TPP)‐modified DNA origami nanostructure for TIPE‐2 mRNA delivery (TPP‐DNA Origami@TIPE‐2) to restore the metabolic‐immune homeostasis of microglia. Experiments demonstrated that this nanoplatform exhibits high structural stability (<5% size variation over 48 h) and efficient mRNA loading (82.6%), markedly enhances mitochondrial function (OCR increased by 76.3%), promotes M2 microglial polarization (CD206 + cells increased 2.5‐fold), and suppresses inflammatory signaling (IL‐1β reduced 3.8‐fold). In a murine ICH model, TPP‐DNA Origami@TIPE‐2 significantly improved neurological outcomes via activation of the PGC‐1α pathway, while single‐cell RNA sequencing revealed coordinated metabolic and immune reprogramming at the microglial subpopulation level. Collectively, this work establishes an organelle‐targeted mRNA nanotherapeutic strategy for precise modulation of neuroinflammation, addressing key barriers to mRNA delivery in the central nervous system.