A BBB‐Penetrating Fullerene Mediates Recovery from Intracerebral Hemorrhage via Dually Promoting Hematoma Clearance and Neuroprotection

Abstract

Current pharmacologic intervention for intracerebral hemorrhage (ICH) is severely limited by insufficient blood-brain barrier (BBB) penetration and complicated secondary injury mechanisms. To address this, we developed a multi-pronged therapeutic strategy for ICH utilizing a BBB-penetrating tetra malonic acid derivative of C₇₀ fullerene (TMF), which dually accelerates hematoma clearance and mitigates perihematomal damage. Following intravenous administration, TMF crossed the BBB via clathrin-mediated endocytosis in cerebral microvascular endothelial cells and accumulated in brain tissue. It promoted hematoma resolution and improved motor deficits in both zebrafish and mouse ICH models. Mechanistically, TMF reduced microglial oxidative stress, leading to its polarization toward the M2 phenotype. This shift enhanced phagosome signaling and degradation functions while attenuating neuroinflammation. Additionally, TMF exhibited direct neuroprotection by resisting oxidative stress, iron toxicity, and apoptosis, collectively constituting its pleiotropic therapeutic mechanisms. In summary, this study overcomes the major challenges in ICH therapeutics, offering a promising candidate for clinical intervention.