Antithrombotic therapy is confronted with short half-lives
of thrombolytic
agents and high bleeding risks. Challenges remain in the development
of drug delivery systems for thorough destruction of thrombi and timely
restoration of blood flow while minimizing side effects. Herein, polydopamine
capsule-like micromotors with urokinase (uPA) loadings and Arg-Gly-Asp
(RGD) grafts (r-u@PCM) were constructed using rod-shaped bacteria
as the template, and one single opening was created on each capsule
through bacterial ghost (BG) formation. Glucose oxidase and catalase
were encapsulated in the large cavity of microcapsules, and their
successive oxidation of glucose produced O2 bubbles, which
ejected out through the single opening to propel the motion of r-u@PCM.
In vitro targeting testing of r-u@PCM shows significant higher accumulations
on the activated platelets than those without RGD grafts (u@PCM, 7
folds) or without enzyme loadings (r-u@PC, 11 folds). Compared with
the major distribution of r-u@PC on the clot surface, r-u@PCM efficiently
penetrates into clots with dense fibrin networks, and near-infrared
(NIR) irradiation (r-u@PCM/NIR) promotes thrombus infiltration through
increasing uPA release and thermolysis of the networks. Pharmacokinetic
study shows that the loading of uPA in r-u@PCM extends the terminal
half-life from 24 min to 5.5 h and the bioavailability increased 13
times. In a hindlimb venous thrombosis model, r-u@PCM/NIR treatment
promotes uPA accumulations in thrombi and disrupts all the thrombi
after 8 h with a full recovery of blood flows. Effective thrombolysis
is also achieved even after reducing the uPA dose 5 times. Thus, this
is the first attempt to fabricate rod-shaped microcapsule motors through
a biologically derived method, including bacterial templating and
BG formation-induced opening generation. r-u@PCM/NIR treatment promotes
thrombolysis through the photothermal effect, self-propelled infiltration
into thrombi, and accelerated local release of uPA, providing a prerequisite
for reducing uPA dose and bleeding side effects.
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