Nanoparticle delivery systems mitigate hemorrhagic complications following tPA-induced thrombolysis

Ischemic stroke remains a leading global cause of mortality and long-term disability, with current therapeutic strategies limited to mechanical thrombectomy and intravenous tissue plasminogen activator (tPA) administration. Although tPA improves clinical outcomes via timely reperfusion, its clinical utility is limited by life-threatening complications such as cerebral hemorrhage and edema. This review critically examines the limitations of conventional tPA therapy and proposes nanoparticle-based delivery systems as transformative strategies to enhance thrombolytic precision and safety. Engineered nanoparticles address key challenges by (1) stabilizing tPA against rapid degradation, extending its plasma half-life; (2) enabling thrombus-targeted delivery through surface modifications (e.g., arginine-glycine-aspartic acid (RGD) peptides), thereby reducing systemic bleeding risks; and (3) conferring neuroprotection via reactive oxygen species (ROS) scavenging and inflammation modulation. Emerging platforms—including PEGylated liposomes, gold nanoparticles, platelet-mimetic carriers, and ultrasound-responsive systems—demonstrate enhanced thrombolytic efficacy when combined with tPA. Notably, ultrasound-triggered nanoparticle activation synergistically improves clot penetration while mitigating ischemia-reperfusion injury. Consequently, these multifunctional nanoplatforms represent a paradigm shift in stroke management, offering safer and more effective strategies to optimize thrombolytic therapy.