Treatment of severe sepsis with nanoparticulate cell-free DNA scavengers

Abstract

Severe sepsis represents a common, expensive, and deadly health care issue with limited therapeutic options. Gaining insights into the inflammatory dysregulation that causes sepsis would help develop new therapeutic strategies against severe sepsis. In this study, we identified the crucial role of cell-free DNA (cfDNA) in the regulation of the Toll-like receptor 9–mediated proinflammatory pathway in severe sepsis progression. Hypothesizing that removing cfDNA would be beneficial for sepsis treatment, we used polyethylenimine (PEI) and synthesized PEI-functionalized, biodegradable mesoporous silica nanoparticles with different charge densities as cfDNA scavengers. These nucleic acid–binding nanoparticles (NABNs) showed superior performance compared with their nucleic acid–binding polymer counterparts on inhibition of cfDNA-induced inflammation and subsequent multiple organ injury caused by severe sepsis. Furthermore, NABNs exhibited enhanced accumulation and retention in the inflamed cecum, along with a more desirable in vivo safety profile. Together, our results revealed a key contribution of cfDNA in severe sepsis and shed a light on the development of NABN-based therapeutics for sepsis therapy, which currently remains intractable.

Cationic Nanostructures for the Treatment of Inflammatory Bone Loss

“…Polyamidoamine dendrimers (PAMAM-G3) are soluble, cationic nucleic acid-binding polymers (NABPs) that prevent TLR activation and inhibit in ammation, and have demonstrated therapeutic e cacy in preclinical studies of acute liver failure, 17 lupus, 18 cancer metastasis, 19 in uenza infection, 20 and sepsis. 21 We have shown that insoluble cationic nucleic acid-binding nanoparticles (NABNs) exhibit greater therapeutic e cacy than soluble NABPs and lower toxicity in murine sepsis and rheumatoid arthritis models. [21][22][23] Here we develop NABNs speci cally for periodontitis by coating bone-mimicking selenium-doped hydroxyapatite nanoparticles (SeHANs) with PAMAM-G3, and compare the therapeutic activity of these NABNs with that of soluble PAMAM-G3 polymers in vitro and in a ligature-induced periodontitis murine model.…”

Nanotools for Sepsis Diagnosis and Treatment

“…Histopathological and biochemical data of cecal ligation and puncture (CLP)-induced severe sepsis mice revealed that injected PEI-MSNPs accumulated and retained in the inflamed cecum, blocked the proinflammatory response and protected mice against multiple organ injury with negligible toxic effects in vivo. [148] The NP-based gene therapy described above, as well as the NP-enable cell therapy described earlier, [115] uncover the multitude of emerging opportunities nanomedicine can offer for the management of sepsis.…”

“…Inspired by this principle, Dawulieti et al synthesized polyethylenimine (PEI)-functionalized mesoporous silica NPs (MSNPs, 150 nm in size) which bound to proinflammatory nucleic acids and scavenged cfDNA. [148] The scavenging activity of PEI-MSNPs resulted in the inhibition of cfDNA-triggered inflammation, the reduction of serum cytokines (TNF-, IL-6, and MCP-1) and elimination of organ damage. Histopathological and biochemical data of cecal ligation and puncture (CLP)-induced severe sepsis mice revealed that injected PEI-MSNPs accumulated and retained in the inflamed cecum, blocked the proinflammatory response and protected mice against multiple organ injury with negligible toxic effects in vivo.…”

Circulating Free DNA and Its Emerging Role in Autoimmune Diseases

“…The treatment with DNase was shown to be active in several immune-mediated experimental models through the breaking of NETs and the consequent pro-inflammatory activity [ 115 , 116 ]. Another promising line of work is focused on the development of nucleic acid-binding polymers (NABPs), which can scavenge proinflammatory cfDNA to modulate inflammation at the injured site [ 117 , 118 ]. Of note, the therapeutic potential of cfDNA in this context of research should be further explored in the near future.…”