Thrombotic disorders-such as ischemic stroke, heart attack, pulmonary embolism, and deep vein thrombosis-are principal contributors to global mortality. However, conventional thrombolytic therapies are often constrained by poor targeting and limited control over the local coagulation environment. In short, they may increase the risk of systemic bleeding and fail to reduce the chance of future clotting at the thrombotic site-thus reducing efficacy and increasing adverse events.
In response to this challenge, researchers in China have developed a novel silicon-based nanothrombolytic therapy that achieves efficient thrombus clearance and in situ regulation of the coagulation microenvironment while minimizing systemic bleeding risk.
The study was led by Prof. SHI Jianlin from the Shanghai Institute of Ceramics of the Chinese Academy of Sciences (CAS), in collaboration with scientists from the Shanghai Tenth People's Hospital, the Shanghai Advanced Research Institute of CAS, and Liaoning Cancer Hospital. The findings were published in Science Advances on February 6.
This innovative therapeutic strategy combines enzymatic clot dissolution with intelligent microenvironment reprogramming. Specifically, urokinase, a clinical thrombolytic drug, was assembled with a hydrogenated silicene (SiH) nanosheet and fibrinogen, a substrate of the coagulation reaction, to stimulate thrombolysis.
According to the researchers, the SiH nanosheet plays three important roles in the enhanced thrombolysis: 1) It blocks the functional sites of urokinase to durably inhibit its activity during circulation, thereby preventing systemic bleeding; 2) Self-degradation of the SiH nanosheet triggers re-activation of urokinase at the thrombotic site; and 3) In situ hydrogen generation enables regulation of the prothrombotic microenvironment to inhibit further thrombosis.
This microenvironment-adaptive thrombolysis strategy offers a promising paradigm for the precise management of thrombotic emergencies.
Molecular docking analyses revealed that SiH nanosheets can interact with the catalytic site of urokinase. Subsequent experiments also confirmed that SiH effectively suppresses urokinase activity by more than 95%. Using in situ Fourier transform infrared spectroscopy, the researchers then dynamically tracked SiH degradation in real time. Notably, as SiH gradually decomposed, urokinase activity was progressively restored within four hours, enabling controlled recovery of thrombolytic function and ultimately achieving efficient thrombus clearance.
Meanwhile, SiH decomposition was accompanied by continuous hydrogen generation, which reshaped the coagulation microenvironment through a dual mechanism: First, hydrogen activated endogenous antioxidant defenses to alleviate oxidative stress-induced endothelial injury and reduce the expression of ICAM-1, PAI-1, and von Willebrand factor (vWF). At the same time, it promoted endothelial repair and limited collagen-exposure-driven platelet adhesion and activation-ultimately exerting an anticoagulant effect.
These effects were further validated in vivo, where the nanothrombolytic demonstrated both precise regulation of the coagulation microenvironment and robust thrombolytic efficacy without increasing systemic bleeding risk.
Together, this synergistic strategy establishes a promising platform for next-generation precision thrombolytics that dynamically integrate clot dissolution with local microenvironmental reprogramming.
Schematic illustration showing the targeting, anti-coagulation, and thrombolysis mechanisms of the nanothrombolytic (SiH@UK/Fib) against arterial embolism (Image by LIN Han)
