Intrinsic Biotaxi Solution Based on Blood Cell Membrane Cloaking Enables Fullerenol Thrombolysis In Vivo

Abstract

We report the construction of blood cell membrane cloaked mesoporous silica nanoparticles for delivery of nanoparticles [fullerenols (Fols)] with fibrinolysis activity which endows the active Fol with successful thrombolysis effect in vivo. In vitro, Fols present excellent fibrinolysis activity, and the Fol with the best fibrinolysis activity is screened based on the correlation between Fols’ structure and their fibrinolysis activity. However, the thrombolytic effect in vivo is not satisfactory. To rectify the unsatisfactory situation and avoid the exogenous stimuli, a natural blood cell membrane cloaking strategy with loading the active Fol is chosen to explore as a novel thrombolysis drug. After cloaking, the therapeutic platform prolongs blood circulation time and enhances the targeting effect. Interestingly, compared with platelet membrane cloaking, red blood cell (RBC) membrane cloaking demonstrates stronger affinity with fibrin and more enrichment at the thrombus site. The Fol with RBC cloaking shows quick and efficient thrombolysis efficacy in vivo with less bleeding risk, more excellent blood compatibility, and better biosafety when compared with the clinical drug urokinase (UK). These findings not only validate the blood cell membrane cloaking strategy as an effective platform for Fol delivery on thrombolysis treatment, but also hold a great promising solution for other active nanoparticle deliveries in vivo.

Cell membrane-derived vesicles for delivery of therapeutic agents

“…Because cell membranes are constructed from lipids, proteins and carbohydrates, which are biodegradable and found naturally in the body, cell membrane coatings may reduce the cellular toxicity of the core material. Among the nanoparticles that have been coated with cell membranes are metal 57 , 58 , carbon 59 , and gold 60 nanoparticles. Cell membrane coating has been reported to reduce plasma protein opsonization and phagocytosis by immune cells, thereby prolonging the circulation time of the core material 61 .…”

“… Core particle Purpose Disease Ref. PLGA Immune evasion Tumor-targeting Mouse liver cancer (H22) 23 Immune evasion Subendothelium binding Pathogen adhesion Coronary restenosis Systemic bacterial infection 59 Magnetic nanoparticles Homing to atherosclerotic sites Atherosclerosis 44 , 84 Specific clearance of anti-platelet antibodies Immune thrombocytopenia purpura 85 Immune evasion Tumor-targeting Mouse breast cancer (4T1) 82 Polypyrrole Immune evasion Tumor-targeting Human liver cancer (Huh 7) 81 Mesoporous silica Enhance blood retention Improving target accumulation Carotid thrombosis 59 …”

Development and Testing of Thrombolytics in Stroke

“…117 Loading thrombolytics into blood cell membrane-based particles showed improved therapeutic efficacy over free thrombolytics in animal ischemic stroke and thrombosis models, while preserving coagulation profiles and having fewer bleeding complications. 128,129 Blood cell membrane-based nanoparticles coated with tPA have led to a significantly better neurological score and survival rate, with a practically unchanged coagulation profiles. Although many studies are exploring the encapsulation of thrombolytics in stroke treatment, 117,118 the translation to clinical practice is still pending.…”

Thrombolytic Agents: Nanocarriers in Targeted Release

“…As a novel nanoparticle modification strategy, it has also been applied to thrombolytic therapy in recent years. Chen and colleagues demonstrated that erythrocyte membrane-coated mesoporous silica nanoparticles effectively prolonged the blood circulation time and exhibited superior targeting of fibrin (Figure 5A,B) [75]. Xu et al designed a platelet bionic nanoparticle conjugated with rtPA using platelet membrane to improve biodistribution and achieve a clot-targeting thrombolytic therapy (Figure 5C,D) [76].…”