Retrievable tPA-anchored nanorobots may improve thrombolysis in ischaemic stroke

Researchers in a cross-disciplinary team from the Chinese University of Hong Kong (CUHK) have developed retrievable nanorobots anchored with tissue plasminogen activator (tPA-nbots) that increase thrombolysis rates by 20 times with a 42-fold lower tPA dose than pure tPA treatment. With a catheter-assisted magnetic navigation system, the tPA-nbots recanalized distal and small vessel branches, showing potential in reducing brain damage and treatment side effects among patients with ischaemic stroke.

Moreover, the use of laser speckle contrast imaging (LSCI) for real-time tracking and navigation of nanorobot microswarms ensured delivery efficiency and biomedical safety in vascular environments. [Sci Robot 2024;9:eadh1978]

The tPA-nbots, comprising 300 nm Fe₃O₄@mSiO₂ magnetic spheres chemically bound with tPA, are delivered through a catheter to the target site, where the microswarm is remotely guided to the thrombus within submillimetre-sized vessels via magnetic actuation with an imaging system. Following tPA-mediated thrombolysis, the nanorobots are retrieved. [Sci Adv 2024;10:eadk8970]

Combining mechanical interaction and chemical etching, the tPA-nbot system can facilitate thrombolysis in peripheral and small vessels, according to Professor Simon Yu of the Department of Imaging and Interventional Radiology, CUHK.

In laboratory testing, tPA-nbots 1 mg (tPA dose, 15 μg) dissolved an artificial blood clot 6.5 mm in length in a vessel model resembling the M3 segment (diameter, 1.5 mm) in 18 min. The thrombolysis rate with tPA-nbots was 0.638 mm³/min, outperforming pure tPA (625 μg) with a thrombolysis rate of 0.0318 mm³/min.

In ex vivo thrombolysis in human placenta, tPA-nbots 5 mg were directed towards a blood clot 6 mm in length in a branched vessel (diameter, 1.5 mm) with an artificial blood flow of 20 mm/s. Under magnetic control (field strength, 65 mT; frequency, 3 Hz), the thrombolysis rate was 0.46 mm³/min, with a retrieval rate of about 80 percent. In vivo thrombolysis with tPA-nbots were further verified in male Sprague-Dawley rats and a New Zealand white rabbit.

tPA-nbots demonstrated biocompatibility with minimal risk of side effects. Mice injected with 200 μL of tPA-nbots (5, 10 or 25 mg/mL) or control saline maintained normal blood counts on days 4 and 15. At 1 week after tPA-nbots injection at 10 mg/kg, histopathological examination revealed no evidence of tissue damage or tPA-nbot accumulation in the heart, liver, spleen, lung, and kidney of treated mice.

To improve nanorobot delivery precision, the researchers utilized noninvasive, high-resolution LSCI for real-time tracking and navigation of microswarms in various vascular settings, including in vitro vessel models, ex vivo human placenta and in vivo animals. In a male Sprague-Dawley rat injected with magnetic nanoparticles 200 µg, the LSCI-guided microswarm travelled through the femoral vein for a total distance of 16.8 mm, with 85 percent retrieval. The tracking duration was up to 35 min. [Sci Robot 2024;9:eadh1978] 

“Incorporating LSCI-guided delivery with catheterization could allow accurate [delivery and] navigation of nanorobot microswarms during interventional procedures,” concluded the researchers.

Ex vivo thrombolysis with tPA-nbot microswarm in human placenta model under catheter-assisted magnetic actuation system. Adapted from Sci Adv 2024;10:eadk8970.