CpG and Rutin Co‐Loaded DNA Tetrahedra for Targeted Therapy of Intracerebral Hemorrhage: Synergistic Hematoma Clearance and Neuroinflammation Inhibition

Abstract Intracerebral hemorrhage (ICH) presents a formidable challenge due to its high mortality and disability rates, primarily attributed to cerebral hematoma formation and ensuing neuroinflammation. Swift hematoma removal is paramount for prognosis, yet existing interventions carry risks and limitations. Notably, elevated CD47 expression on hematoma‐associated RBC triggers a “don't eat me” signal, impeding hematoma clearance, while microglial/macrophage erythrophagocytosis exacerbates oxidative stress and the RBC lysate evokes neuroinflammation. To address this conundrum, a multifunctional nanomedicine (TD‐CFR), employing DNA tetrahedra (TD) as a carrier for ICH treatment is introduced. The investigations reveal that CpG enhances the phagocytosis of CD47‐expressing RBC by microglia/macrophages via lipid metabolism modulation. Integration of CpG into TD preserves its pro‐phagocytic efficacy, while TD's double‐stranded region enables efficient encapsulation of Rutin, a potent anti‐inflammatory and antioxidant flavonoid. Capitalizing on disrupted blood‐brain barrier integrity at the hemorrhage site, TD‐CFR achieves robust enrichment within cerebral hematoma post‐intravenous administration, augmented by folate receptor‐mediated targeting of microglia/macrophages. Efficacy assessments in mouse and rabbit ICH models confirm TD‐CFR's therapeutic benefits, including hematoma clearance, neuroinflammation suppression, and brain function restoration. Leveraging TD's high biosafety profile and dual active ingredient loading capacity, the study unveils a promising drug treatment paradigm for ICH.