Polycationic Nanofibers for Nucleic Acid Scavenging

Jackman, Jennifer; Juwarker, Hemraj; Poveromo, Luke; Levinson, Howard; Leong, Kam W.; Sullenger, Bruce A.

doi:10.1021/acs.biomac.6b01236

Cited by 15 publications

(9 citation statements)

References 33 publications

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“…The ability of HDMBr to bind free plasma mtDNA could be a large part of its protective mechanism. This is also supported by recent studies in which NASPs were immobilized on microspheres or incorporated into a nanofiber mesh and co-incubated with cells and CpG DNA to produce cellular protection ( 62 , 63 ).…”

Section: Discussionsupporting

confidence: 67%

Scavenging Circulating Mitochondrial DNA as a Potential Therapeutic Option for Multiple Organ Dysfunction in Trauma Hemorrhage

et al. 2018

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Trauma is a leading cause of death worldwide with 5.8 million deaths occurring yearly. Almost 40% of trauma deaths are due to bleeding and occur in the first few hours after injury. Of the remaining severely injured patients up to 25% develop a dysregulated immune response leading to multiple organ dysfunction syndrome (MODS). Despite improvements in trauma care, the morbidity and mortality of this condition remains very high. Massive traumatic injury can overwhelm endogenous homeostatic mechanisms even with prompt treatment. The underlying mechanisms driving MODS are also not fully elucidated. As a result, successful therapies for trauma-related MODS are lacking. Trauma causes tissue damage that releases a large number of endogenous damage-associated molecular patterns (DAMPs). Mitochondrial DAMPs released in trauma, such as mitochondrial DNA (mtDNA), could help to explain part of the immune response in trauma given the structural similarities between mitochondria and bacteria. MtDNA, like bacterial DNA, contains an abundance of highly stimulatory unmethylated CpG DNA motifs that signal through toll-like receptor-9 to produce inflammation. MtDNA has been shown to be highly damaging when injected into healthy animals causing acute organ injury to develop. Elevated circulating levels of mtDNA have been reported in trauma patients but an association with clinically meaningful outcomes has not been established in a large cohort. We aimed to determine whether mtDNA released after clinical trauma hemorrhage is sufficient for the development of MODS. Secondly, we aimed to determine the extent of mtDNA release with varying degrees of tissue injury and hemorrhagic shock in a clinically relevant rodent model. Our final aim was to determine whether neutralizing mtDNA with the nucleic acid scavenging polymer, hexadimethrine bromide (HDMBr), at a clinically relevant time point in vivo would reduce the severity of organ injury in this model. Conclusions: We have shown that the release of mtDNA is sufficient for the development of multiple organ injury. MtDNA concentrations likely peak at different points in the early postinjury phase dependent on the degree of isolated trauma vs combined trauma and hemorrhagic shock. HDMBr scavenging of circulating mtDNA (and nuclear DNA, nDNA) is associated with rescue from severe multiple organ injury in the animal model. This suggests that HDMBr could have utility in rescue from human trauma-induced MODS.

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Section: Discussionsupporting

confidence: 67%

Scavenging Circulating Mitochondrial DNA as a Potential Therapeutic Option for Multiple Organ Dysfunction in Trauma Hemorrhage

et al. 2018

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“…The following study further demonstrated that using these NA-binding polymers to limit NA-induced inflammation is effective in some inflammatory and autoimmune diseases ( 17 – 20 ). Considering the toxicity of cationic materials administered systemically, a local ( 31 ) or ex vivo method ( 32 ) using immobilized polycations to remove DAMP molecules may be a better choice for easy clinical translation.…”

Section: Discussionmentioning

confidence: 99%

Topical nanoparticles interfering with the DNA-LL37 complex to alleviate psoriatic inflammation in mice and monkeys

Liang

Yan

et al. 2020

Sci. Adv.

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Cell-free DNA (cfDNA) released from damaged or dead cells combines with LL37 and is converted into an immune response activator to exacerbate psoriasis. Here, we show that cationic nanoparticles (cNPs) efficiently compete for DNA from the DNA-LL37 immunocomplex and inhibit DNA-LL37-induced cell activation. Using phenotypical images, psoriasis area and severity index scoring, histology, and immunohistochemical analysis, we demonstrate that topical application of cNPs on psoriasiform skin of a mouse model relieves psoriatic symptoms. It is noteworthy that the results were confirmed in a cynomolgus monkey model. Moreover, topically administrated cNPs showed low in vivo toxicity because of their retention in skin. Mechanistic analyses of cytokine expression in the psoriatic site, cfDNA levels in circulation and inflamed skin, skin permeation, and biodistribution of cNPs also matched the therapeutic outcomes. Therefore, we present a previously unidentified strategy of nanomedicine to treat skin inflammatory diseases, which demonstrates great potential for clinical application.

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“…Using these nucleic acid-binding polymers (NABP) to remove the DAMP molecules, we had demonstrated that the scavenging approach works in animal models of CpG-induced or RNA-induced acute liver injury 19 , thrombosis 29 , and SLE 20 , 30 . To reduce toxicity, we had immobilized the NABP on fibrous membrane to remove the DAMP molecules in a local 31 or ex vivo manner 32 . Motivated by the high NA-binding capacity of the immobilized configuration of NABP in these recent studies, we propose to use cNP as a DAMP scavenger, which has not been studied before, for RA treatment.…”

Section: Discussionmentioning

confidence: 99%

Cationic nanoparticle as an inhibitor of cell-free DNA-induced inflammation

et al. 2018

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Cell-free DNA (cfDNA) released from damaged or dead cells can activate DNA sensors that exacerbate the pathogenesis of rheumatoid arthritis (RA). Here we show that ~40 nm cationic nanoparticles (cNP) can scavenge cfDNA derived from RA patients and inhibit the activation of primary synovial fluid monocytes and fibroblast-like synoviocytes. Using clinical scoring, micro-CT images, MRI, and histology, we show that intravenous injection of cNP into a CpG-induced mouse model or collagen-induced arthritis rat model can relieve RA symptoms including ankle and tissue swelling, and bone and cartilage damage. This culminates in the manifestation of partial mobility recovery of the treated rats in a rotational cage test. Mechanistic studies on intracellular trafficking and biodistribution of cNP, as well as measurement of cytokine expression in the joints and cfDNA levels in systemic circulation and inflamed joints also correlate with therapeutic outcomes. This work suggests a new direction of nanomedicine in treating inflammatory diseases.

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Polycationic Nanofibers for Nucleic Acid Scavenging

Cited by 15 publications

References 33 publications

Scavenging Circulating Mitochondrial DNA as a Potential Therapeutic Option for Multiple Organ Dysfunction in Trauma Hemorrhage

Scavenging Circulating Mitochondrial DNA as a Potential Therapeutic Option for Multiple Organ Dysfunction in Trauma Hemorrhage

Topical nanoparticles interfering with the DNA-LL37 complex to alleviate psoriatic inflammation in mice and monkeys

Cationic nanoparticle as an inhibitor of cell-free DNA-induced inflammation

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