Therapeutic siCCR2 Loaded by Tetrahedral Framework DNA Nanorobotics in Therapy for Intracranial Hemorrhage

Modulating microglial polarization is a potential strategy to assuage secondary brain injury caused by intracranial hemorrhage (ICH). However, despite decades of effort, effective therapies targeting microglia for ICH are still lacking. Here, a nanorobotic, tetrahedral framework nucleic acid (tFNA), is successfully synthesized and designed to carry C‐C chemokine receptor 2 (siCCR2) for use in in vitro hemin‐induced and in vivo collagenase‐induced ICH models. This nanoscale complex (tFNA‐siCCR2), which possesses biocompatibility, editability, and structural stability, exhibits a favorable effect in inhibiting the expression of CCR2. After treatment with tFNA‐siCCR2, hematoma absorption is accelerated, and neurological inflammation is mitigated by decreasing levels of proinflammatory cytokines, while increasing the release of anti‐inflammatory factors. Consequently, the neurological deficits of mice with ICH improve. These results indicate that inhibiting CCR2 expression during the acute phase of ICH polarizes microglia towards a therapeutic subtype, and restores neurological function, which demonstrates that tFNA has a promising ability to transfer siCCR2 for treating ICH. Tetrahedral framework nucleic acid (tFNA)‐C‐C chemokine receptor 2 (siCCR2) is investigated as therapy for intracranial hemorrhage (ICH) mice. Four specific designed DNA single strands are selfassembled to construct a tetrahedron and carry siCCR2 to inhibit the expression of CCR2 in microglia. By regulating the polarization of microglia from M1 to M2, tFNA‐siCCR2 accelerates absorption of hematoma, thereby reducing motor nerve function impairment in mice with ICH.