Synergistic Integration and Pharmacomechanical Function of Enzyme‐Magnetite Nanoparticle Swarms for Low‐Dose Fast Thrombolysis

Abstract

Magnetic micro‐/nanoparticles are extensively explored over the past decade as active diagnostic/therapeutic agents for minimally invasive medicine. However, sufficient function integration on these miniaturized bodies toward practical applications remains challenging. This work proposes a synergistic strategy via integrating particle functionalization and bioinspired swarming, demonstrated by recombinant tissue plasminogen activator modified magnetite nanoparticles (rtPA‐Fe3O4 NPs) for fast thrombolysis in vivo with low drug dosage. The synthesized rtPA‐Fe3O4 NPs exhibit superior magnetic performance, high biocompatibility, and thrombolytic enzyme activity. Benefiting from a customized magnetic operation system designed for animal experiments and preclinical development, these agglomeration‐free NPs can assemble into micro‐/milli‐scale swarms capable of robust maneuver and reconfigurable transformation for on‐demand tasks in complex biofluids. Specifically, the spinning mode of the swarm exerts focused fluid shear stresses while rubbing on the thrombus surface, constituting a mechanical force for clot breakdown. The synergy of the NPs’ inherent enzymatic effect and swarming‐triggered fluid forces enables amplified efficacy of thrombolysis in an in vivo occlusion model of rabbit carotid artery, using lower drug concentration than clinical dosage. Furthermore, swarming‐enhanced ultrasound signals aid in imaging‐guided treatment. Therefore, the pharmacomechanical NP swarms herein represent an injectable thrombolytic tool joining advantages of intravenous drug therapy and robotic intervention.

Application of Nanotechnology in Thrombus Therapy

“…The NPs, manipulated by a customized rotating permanent magnet system, not only achieved targeted thrombolysis of rtPA but also the synergistic rotational motion of the NP cluster enhanced the fluid shear force acting on the thrombus surface; thus, accelerating the dissolution of the thrombus and amplifying the thrombolytic efficacy of the drug ( Figure a,b). [ 84 ] Meanwhile, histological analysis of rabbit carotid artery sections revealed that the mechanical force of this magnetite NP population did not cause damage to the vessel wall and had a high safety and clinical translation potential. In addition, based on Fe 3 O 4 , Prilepskii et al.…”

“…Moreover, as the thrombus is located right in the lumen of the blood vessel, drug delivery to it appears to be more convenient than to the tumor and shows larger therapeutic potential. [82] In the last decade, researchers have developed various nanocarriers, including inorganic particles such as mesoporous silica, [72,83] metal NPs, [84] and organic particles including micelles, [85,86] liposomes, [87,88] and polymers. [89,90] By functionally modifying these nanocarriers, it is possible to achieve targeted delivery of thrombotic medicines.…”

“…Various materials have been developed to construct nanocarriers, including organic substances (liposomes, [87,88] polymers, [89,90,141] etc. ), inorganic substances (iron, [84] etc. ), and natural blood cells, [142] each of which will be described here.…”

“…Some researchers have also investigated using the external magnetic field to achieve targeted thrombolytic drug delivery. [84,165] This external field-dependent drug delivery system may apply to treating thrombosis at extremity sites. In contrast, precise delivery of therapeutic drugs may be challenging for thrombosis at complex sites.…”

“…The detected signals are distributed on the entire NP. Scale bar = 200nm.Reprinted with permission from ref [84]. .…”