Theranostic Nucleic Acid Binding Nanoprobe Exerts Anti-inflammatory and Cytoprotective Effects in Ischemic Injury

Abstract

Extracellular nucleic acids are proinflammatory molecules that have been implicated in a diverse range of diseases. We report here the development of a multivalent nucleic acid scavenging nanoprobe, where the fluorochrome thiazole orange (TO) is conjugated to a polymeric 40 kDa dextran carrier. Dextran-TO (Dex-TO) has nanomolar affinity for mammalian and bacterial nucleic acids and attenuates the production of inflammatory cytokines from activated macrophages exposed to DNA and RNA. Mice with myocardial ischemia reperfusion that were treated with Dex-TO showed a decrease in myocardial macrophage infiltration at 24 hours (p<0.05) and a decrease in infarct size (18% ± 9%, p<0.01) on day 7. Dex-TO allows sites of injury to be identified with fluorescence imaging, while simultaneously exerting an anti-inflammatory and cytoprotective effect. Dex-TO could be of significant diagnostic and therapeutic (theranostic) utility in a broad range of conditions including ischemia, trauma, burns, sepsis and autoimmune disease.

Extracellular vesicles derived from Krüppel-Like Factor 2-overexpressing endothelial cells attenuate myocardial ischemia-reperfusion injury by preventing Ly6Chigh monocyte recruitment

“…Recently, new therapies emerged for regulating inflammation. For example, the canakinumab, which inhibits the IL-1β innate immunity pathway, significantly reduced the rate of recurrent cardiovascular events, but had a lower heart-targeting effect 36 ; theranostic nucleic acid-binding nanoprobes were shown to exert anti-inflammatory and cytoprotective effects in ischemic injury 37 ; platelet-targeted delivery of peripheral blood mononuclear cells to the ischemic heart restored cardiac function after I/R injury 38 . Clearly, this field is in its infancy, and a concerted effort is needed to develop effective therapies to modify inflammation rationally.…”

Extracellular miR-146a-5p Induces Cardiac Innate Immune Response and Cardiomyocyte Dysfunction

“…We and others have demonstrated that cellular nucleic acids such as RNA and miRNA are released from the heart following myocardial ischemic injury ( 4 , 5 , 7 , 34 – 36 ). The cellular RNA, once released from the cells, can be highly proinflammatory by inducing cytokine production and innate immune cell activation ( 35 ).…”

“…Inflammation is a key component of myocardial ischemic injury ( 1 ). Studies have shown that nucleic acids such as cellular RNAs, including microRNAs (miRNAs), are released from initial tissue injury within the myocardium ( 2 – 4 ) and may contribute to the increased myocardial inflammation following ischemia-reperfusion (I/R) injury ( 4 , 5 ). Systemic administration of nucleic acid binding nanoprobe ( 5 ) or RNase ( 4 , 6 ) leads to reduced myocardial inflammation and infarction, likely by reducing extracellular (ex) RNA levels.…”

“…Studies have shown that nucleic acids such as cellular RNAs, including microRNAs (miRNAs), are released from initial tissue injury within the myocardium ( 2 – 4 ) and may contribute to the increased myocardial inflammation following ischemia-reperfusion (I/R) injury ( 4 , 5 ). Systemic administration of nucleic acid binding nanoprobe ( 5 ) or RNase ( 4 , 6 ) leads to reduced myocardial inflammation and infarction, likely by reducing extracellular (ex) RNA levels. Moreover, several of these ex-miRNAs (e.g., ss-miR-146a-5p and miR-133a) induce potent innate immune responses, including cytokine and complement factor production in cultured cells and acute peritonitis after local injection ( 7 , 8 ).…”

Damage-Associated Molecular Patterns in Myocardial Infarction and Heart Transplantation: The Road to Translational Success

“…Others developed a multivalent nucleic acid scavenging nanoprobe, fluorochrome thiazole orange conjugated to a dextran carrier (Dex-TO), to scavenge nucleic acids. Dex-TO was administered intravenously to mice subjected to MI, initially at the onset of IRI and again 4 h later, resulting in a reduced inflammation and a decrease in IS in the Dex-TO treated mice ( 57 ).…”