Abstract
The high mortality and disability rates associated with spontaneous intracerebral hemorrhage (sICH) are primarily attributed to secondary injuries caused by hematoma expansion from continuous bleeding or rehemorrhage. Rapid hemostasis to prevent hematoma progression is critical in clinical emergencies for improving surgical outcomes and patient prognosis. For internal hemorrhages inaccessible to external interventions, especially for sICH, intravenous hemostatic strategies are essential regardless of ultimate surgical eligibility. This study reported a stealth hemostatic anchor system based on peptide-drug conjugates. Tranexamic acid (TXA), a clinically approved antifibrinolytic agent, served as the hemostatic component, while a von Willebrand factor (vMF)-binding peptide (VBP) enabled targeted delivery by specifically binding to (vMF) exposed at vascular injury sites. A plasmin-cleavable linker was incorporated to control TXA release, ensuring site-specific drug activation. The plasmin-responsive peptide-drug conjugate (RPDC) was synthesized by covalently linking TXA to VBP via the plasmin-cleavable linker. In vitro and in vivo experiments verified the targeted hemostatic efficacy of RPDC, especially demonstrating 42% reduction in hematoma volume (P < 0.001 vs. saline; P < 0.05 vs. free TXA) with mitigated peri‑hematomal pathology in the collagenase-induced ICR mouse ICH model. These results highlight the potential of the stealth hemostatic anchor as a precision therapeutic strategy for managing sICH, particularly in cases of internal hemorrhages inaccessible to surgical intervention or visual inspection. The plasmin-dependent targeting mechanism enables precise drug localization at cryptic hemorrhage sites, but further studies in larger animal models are needed to confirm its efficacy. This design offers a theoretical framework for advancing emergency interventions in cerebral hemorrhage and addressing challenges related to inaccessible bleeding sites.