The systemic administration of low-molecular-weight heparin (LMWH) as the standard initial treatment for venous thromboembolism is intended to prevent thrombus growth during the acute phase and prevent thrombus recurrence during the chronic phase. However, precisely controlling the specificity and localization of LMWH presents significant challenges, which has necessitated research into targeted delivery methods. Furthermore, due to different thrombosis mechanisms, tailored pharmacologic interventions are needed, particularly for arterial and venous thrombosis. This study employs proteomics technology to identify fibronectin (FN1) as a specific and highly expressed target protein within the thrombi of patients with cerebral venous thrombosis (CVT). Nanoparticles modified with FN1-targeting peptide cysteine-arginine-glutamic acid-lysine-alanine (CREKA) and encapsulating LMWH (CREKA-LMWH NPs) are further engineered to increase the targeting precision and therapeutic efficacy in the treatment of CVT. The in vitro and in vivo findings indicate that the CREKA-LMWH NPs effectively increase the concentration of LMWH at the thrombus site, which augments the prevention and treatment of thrombus expansion and growth without exacerbating toxic side effects. This proteomics-driven precision selection strategy boosts systemic anticoagulation effectiveness by targeting therapeutic agents to the thrombus microenvironment, offering new potential for personalized treatment by tackling the complexities of thrombus composition and formation.