Active-targeted nano-hemostatic for hemostasis and brain microenvironment optimization in intracerebral hemorrhage therapy.

Intracerebral hemorrhage (ICH) is a life-threatening cerebrovascular disorder characterized by rapid hematoma expansion and secondary neurovascular injury, resulting in high mortality and disability. Current hemostatic drugs lack lesion selectivity and fail to stabilize fragile vasculature, leaving patients vulnerable to secondary rebleeding. To address these limitations, we developed ATHEMO (Active-Targeted HEmostasis and brain Microenvironment Optimizer), a peptide-modified nanoplatform designed for targeted hemostasis and sustained neuroprotection. Incorporating a von Willebrand factor (vWF)-binding sequence, ATHEMO precisely homes to ruptured vessels, where it establishes a stable adhesive interface that halts active bleeding and reinforces vascular integrity. Concurrently, the nanocarrier provides controlled release of quercetin, effectively mitigating oxidative stress, promoting M2-type microglial polarization, and preserving blood-brain barrier function. In a murine ICH model, ATHEMO reduced hematoma volume by nearly 70 %, alleviated cerebral edema, improved perfusion, and restored both cognitive and motor functions during long-term recovery. Transcriptomic profiling revealed downregulation of inflammatory cascades and enhancement of synaptic signaling, underscoring ATHEMO's dual hemostatic and neuroprotective effects. These findings demonstrate that combining targeted bleeding control with microenvironment regulation offers a precision nanotherapeutic strategy for ICH, potentially translatable to other non-compressible hemorrhagic conditions.