Among cardiovascular diseases, thrombotic diseases such as ischemic heart disease and acute ischemic strokes are the most lethal, responsible by themselves for a quarter of worldwide deaths. While surgical treatments exist, they may not be used in all situations, and systemic thrombolytic drug injection, such as recombinant tissue plasminogen activators (rtPA), often remains necessary, despite serious limitations including short therapeutic window, severe side effects, and failure to address the complex nature of thrombi. This prompted intense research into alternative thrombolytics or delivery methods, including nanomedicine. However, most nanoparticles face issues of stability, biocompatibility, or synthesis robustness; among them, polymeric nanoparticles, though usually versatile and biocompatible, sometimes lack robustness and may involve toxic or complex synthesis. Here, we present polysaccharide hydrogel nanoparticles designed with an improved microemulsion-based approach that allowed a critical size reduction from microparticles to 315 nm nanoparticles. They were decorated with fucoidan, a sulfated polysaccharide capable of high affinity binding to P-selectin, a thrombi biomarker. These nanoparticles exhibited good stability, adequate size, biocompatibility, and targeting capacity and could be loaded with two different drugs, rtPA (fibrin degradation) or DNase I (degradation of neutrophil extracellular traps, or NETs), to exert thrombolysis. Notably, improved synergic thrombolysis was demonstrated on NET-containing thrombi, while in vivo thrombolysis shed light into improved thrombolysis of rtPA-loaded nanoparticles at 50 and 10% the recommended dose without secondary embolization. These safe, robust, and easy-to-make nanoparticles could provide effective delivery strategies for thrombolytic treatments while demonstrating the potential of polysaccharide nanoparticles as drug-delivery agents.