Dual Frequency-Regulated Magnetic Vortex Nanorobots for Thrombolysis

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Due to the non-invasive remote driving and drug loading capabilities of magnetic nanorobots, there are broad application prospects in thrombolytic therapy. Although nanorobots smaller than 100 nanometers are suitable for microvascular systems, their propulsion performance is severely affected due to limited response to magnetic fields.

On October 18, 2024, Cheng Yu and He Bin from Tongji University, along with Fan Haiming from Northwest University, jointly communicated a research paper titled “Dual Frequency-Regulated Magnetic Vortex Nanorobots Empower Nattokinase for Focalized Microvascular Thrombolysis” published online in ACS Nano. This study demonstrates a magnetic vortex nanorobot (NK-MNR) loaded with nattokinase, with an average size of approximately 70nm, exhibiting high saturation magnetization, capable of mechanical propulsion and thermal-responsive thrombolysis under dual-frequency magnetic fields.

The nanorobots are stable in suspension and are magnetically manipulated to assemble into chain-like NK-MNRs, mechanically disrupting and penetrating clots through low-frequency rotating magnetic fields. The magnetic hyperthermia triggered by high-frequency alternating magnetic fields synergistically enhances the thermally induced release of NK and fibrinolysis. Under the dual magnetic energy conversion regulation in the dual-frequency regulated magnetic thrombolysis (fRMT) strategy, the nanorobots achieved an 81.0% vascular recanalization rate in thrombotic mice. In summary, nanorobots with special magnetic vortex characteristics and multi-mode control represent an effective in vivo focused microvascular thrombolysis nanoplatform.

Dual Frequency-Regulated Magnetic Vortex Nanorobots for Thrombolysis

Venous thromboembolism (VTE) often leads to life-threatening diseases such as deep vein thrombosis (DVT) and is a major cause of death worldwide. Clinical treatments for thrombotic diseases include surgical and drug interventions. Although invasive surgeries such as thrombectomy can effectively prolong survival and alleviate thrombus formation symptoms, their application in microvascular embolism is limited by spatial constraints and poses potential radiation risks. Thrombolytic agents are a common and effective strategy in clinical treatment. First-line thrombolytic drug recombinant tissue plasminogen activator (rtPA) primarily improves survival rates by indirectly dissolving fibrin through the activation of plasmin. Cross-linked fibrin is the main component of thrombi, and nattokinase (NK) can directly dissolve fibrin networks, enhancing the release of tPA when forming plasmin for fibrinolysis, making it an effective thrombolytic candidate drug, but it faces issues such as low utilization, off-target circulation, and high bleeding risks. There is an urgent need to develop a controllable local fibrinolytic microvascular thrombolysis strategy for treating VTE.

Figure 1: Combination of Magnetic and Thermal Therapy for Local Thrombolysis (Excerpt from ACS Nano)

In light of the above limitations, relevant scholars are developing externally propelled nanorobots driven by magnetic fields, light, or ultrasound to optimize thrombolytic effects while minimizing potential side effects. Nanorobots can achieve non-contact operation and precise directional movement, enhancing the efficiency and accuracy of local drug delivery and targeted thrombolytic therapy. Light-driven nanorobots provide precise control and efficient movement, but light has poor penetration in deep tissues. Ultrasound-driven nanorobots exhibit excellent biocompatibility and deep tissue penetration, enabling real-time imaging and navigation. However, directional navigation and tissue absorption of ultrasound nanorobots in complex in vivo environments pose challenges.

Magnetic nanorobots possess the advantages of spatiotemporal control and adjustable size, providing an effective method for nanometer-scale deep and precise delivery of thrombolytic agents. Rotating magnetic fields (RMF) activate magnetic nanorobots for magnetic-mechanical thrombolysis and local drug delivery. Through programmed magnetic fields and surface modifications, several adaptive and multifunctional nanorobots have been developed for narrow gaps and channels. For instance, 760nm-sized nanorobots equipped with heparin-like polymer brushes can achieve targeted drug delivery by mechanical disruption of fibrin through motility, enabling controllable thrombolysis under alternating magnetic fields. Furthermore, under high-frequency alternating magnetic fields (AMF), magnetic nanorobots can provide localized heat for magnetothermal-mediated thrombolysis. Ideally, robots smaller than 100nm meet the drug loading requirements of microvascular systems, but their magnetic response is impaired, and propulsion performance and energy conversion in the biophysical environment face challenges.

Figure 2: Characterization of Chain-like NK-MNRs (Excerpt from ACS Nano)

To address the above challenges, the authors developed a nattokinase-loaded magnetic vortex nanorobot (NK-MNR) smaller than 100nm for dual-frequency regulated magnetic thrombolysis (fRMT). NK-MNR integrates magnetic control components and magnetothermal control for drug release, aimed at microvascular thrombolysis. Unlike traditional magnetic nanorobots with linear magnetic moments, the NK-MNR with magnetic spin vortex ground states can effectively respond to dual-frequency magnetic fields, with negligible remanence and coercivity to prevent aggregation. The dual-frequency nanorobots can convert external magnetic energy into mechanical force and heat for thermal-mechanical fibrinolysis. NK-MNR is magnetically directed to assemble into chain-like NK-MNRs, generating magnetic forces (MF) under low-frequency RMF (15Hz) for mechanical disruption and penetration of clots. High-frequency AMF (375kHz) synergistically triggers magnetothermal therapy (MH), releasing NK to dissolve fibrin. By programming a series of different frequencies for the magnetic components, NK-MNRs achieve focal fibrinolysis and thrombolysis under the dual model of the magnetic field.

References:

https://pubs.acs.org/doi/10.1021/acsnano.4c04331

Dual Frequency-Regulated Magnetic Vortex Nanorobots for Thrombolysis

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