Drug‐Free Thrombolysis Mediated by Physically Activated Micro/Nanoparticles

ABSTRACT Thrombus‐associated disorders rank among the world's leading causes of death, with ischemic heart disease and stroke as the main contributors. Systemic administration of fibrinolytic drugs remains the gold standard treatment for thrombotic diseases, but suffers from severe adverse effects and low recanalization rates. For over three decades, nanomedicine has attempted to overcome these limitations through drug vectorization; however, no nanoparticle‐based fibrinolytic formulation has reached clinical approval so far. In this context, physically activated micro/nanoparticles have emerged as promising alternatives. Remotely triggered by light, ultrasound, or magnetic fields, these systems can destabilize thrombi through hyperthermia, mechanical disruption, or chemical reactions, acting on multiple thrombus components beyond fibrin. Nonetheless, since these emergent thrombolytic therapies are often combined with pharmaceutical drugs, including fibrinolytics, their intrinsic thrombolytic performance remains difficult to assess. For the first time, this review focuses exclusively on drug‐free, stimulus‐responsive micro/nanosystems for thrombolysis. Its originality lies in an analytical framework that classifies studies by thrombolytic effect (thermal, mechanical, chemical, or combinations) rather than by particle composition, aiming at clarifying their mechanisms of action, which clot components are affected, and how effective they are in promoting thrombolysis. Finally, translational challenges, including safety and device considerations, are discussed to guide future non‐pharmaceutical thrombolytic therapies.