Authors:

Benjamyn Caldwell

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About Paper:

Chronic inflammatory diseases, such as systemic lupus erythematosus (SLE) or rheumatoid arthritis, arise when immune activation and inflammation are dysregulated. Common drug therapies, such as those based on steroids, effectively reduce acute inflammation, but bring high risks for severe side effects with long-term or high-dose usage needed for these diseases. To this end, recent studies have suggested that small inhibitory oligonucleotides (INH-ODNs) can serve as alternative therapies by inhibiting the initial activation of inflammatory responses and preventing symptoms from spreading.[1] These molecules bind to and inhibit the activation of a target immune receptor with high specificity, making them an ideal candidate for dysfunctional immune system signaling. However, nucleic acids are susceptible to rapid nuclease degradation and have poor cellular uptake, limiting their translation into clinical treatments. To address these challenges, we employ spherical nucleic acid (SNA) nanoparticles for the delivery of INH18 to investigate the hypothesis that a liposomal nanoparticle structure can act as an effective scaffold to improve nucleic acid uptake and delivery. We first construct an amphiphilic conjugate where 3'-thiol INH18 was conjugated to a phospholipid via the stable linker succininimidy! 4-(p-maleimidophenyl)butyrate (SMPB).[3] This amphiphilic conjugate was then anchored into a DOPC liposomal core to form the desired LSNA. This SNA treatment was tested against TLR9-activation-induced inflammation in an inflammation-reporter cell line stimulated with the TLR9 agonist CpG ODN.[2] These cells produce a secreted embryonic alkaline phosphatase (SEAP) signal as a reporter for the activation of the inflammatory pathway, which was measured using commercial assay. Inflammatory cytokine production were also evaluated using enzyme-linked immunosorbent assays (ELISAs). Our results indicate that the INH18 LSNA can effectively suppress both CpG-induced activation and pro-inflammatory cytokine secretion, laying the groundwork for synergistic dual-therapy strategies that combine upstream receptor inhibition by INH-ODNs with the downstream alleviation of inflammation by steroids.

Source:

Northwestern University

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Co-authors:

Benjamyn Caldwell