Exploring the anti-inflammatory and anti-fibrotic activity of NFκB decoy oligodeoxynucleotide-loaded spermine-functionalized acetalated nanoparticles.

Chronic inflammation, oxidative stress, and airway remodelling represent the principal pathophysiological features of chronic respiratory disorders. Inflammation stimuli like lipopolysaccharide (LPS) activate macrophages and dendritic cells, with concomitant M1 polarization and release of pro-inflammatory cytokines. Chronic inflammation and oxidative stress lead to airway remodelling causing irreversible functional and structural alterations of the lungs. Airway remodelling is multifactorial, however, the hormone transforming growth factor-ß (TGF-ß) is one of the main contributors to fibrotic changes. The signalling pathways mediating inflammation and remodelling rely both on the transcription factor nuclear factor-κB (NFκB), underlying the potential of NFκB inhibition as a therapeutic strategy for chronic respiratory disorders. In this study, we encapsulated an NFκB-inhibiting decoy oligodeoxynucleotide (ODN) in spermine-functionalized acetalated dextran (SpAcDex) nanoparticles and tested the in vitro anti-inflammatory and anti-remodelling activity of this formulation. We show that NF-κB ODN nanoparticles counteract inflammation by reversing LPS-induced expression of the activation marker CD40 in myeloid cells and counteracts remodelling features by reversing the TGF-ß-induced expression of collagen I and α-smooth muscle actin in human dermal fibroblast. In summary, our study highlights the great potential of inhibiting NFκB via decoy ODN as a therapeutic strategy tackling multiple pathophysiological features underlying chronic respiratory conditions.

Neural Tracing Protein-Functionalized Nanoparticles Capable of Fast Retrograde Axonal Transport in Live Neurons.

Neural tracing proteins like horseradish peroxidase-conjugated wheat germ agglutinin (WGA-HRP) can target the central nervous system (CNS) through anatomic retrograde transport without crossing the blood-brain barrier (BBB). Conjugating WGA-HRP to nanoparticles may enable the creation of BBB-bypassing nanomedicine. Microfluidics and two-photon confocal microscopy is applied to screen nanocarriers for transport efficacy and gain mechanistic insights into their interactions with neurons. Protein modification of gold nanoparticles alters their cellular uptake at the axonal terminal and activates fast retrograde transport. Trajectory analysis of individual endosomes carrying the nanoparticles reveals a run-and-pause pattern along the axon with endosomes carrying WGA-HRP-conjugated gold nanoparticles exhibiting longer run duration and faster instantaneous velocity than those carrying nonconjugated nanoparticles. The results offer a mechanistic explanation of the different axonal transport dynamics as well as a cell-based functional assay of neuron-targeted nanoparticles with the goal of developing BBB-bypassing nanomedicine for the treatment of nervous system disorders.

Recent trends of NFκB decoy oligodeoxynucleotide-based nanotherapeutics in lung diseases.

Nuclear factor κB (NFκB) is a unique protein complex that plays a major role in lung inflammation and respiratory dysfunction. The NFκB signaling pathway, therefore becomes an avenue for the development of potential pharmacological interventions, especially in situations where chronic inflammation is often constitutively active and plays a key role in the pathogenesis and progression of the disease. NFκB decoy oligodeoxynucleotides (ODNs) are double-stranded and carry NFκB binding sequences. They prevent the formation of NFκB-mediated inflammatory cytokines and thus have been employed in the treatment of a variety of chronic inflammatory diseases. However, the systemic administration of naked decoy ODNs restricts their therapeutic effectiveness because of their poor pharmacokinetic profile, instability, degradation by cellular enzymes and their low cellular uptake. Both structural modification and nanotechnology have shown promising results in enhancing the pharmacokinetic profiles of potent therapeutic substances and have also shown great potential in the treatment of respiratory diseases such as asthma, chronic obstructive pulmonary disease and cystic fibrosis. In this review, we examine the contribution of NFκB activation in respiratory diseases and recent advancements in the therapeutic use of decoy ODNs. In addition, we also highlight the limitations and challenges in use of decoy ODNs as therapeutic molecules, cellular uptake of decoy ODNs, and the current need for novel delivery systems to provide efficient delivery of decoy ODNs. Furthermore, this review provides a common platform for discussion on the existence of decoy ODNs, as well as outlining perspectives on the latest generation of delivery systems that encapsulate decoy ODNs and target NFκB in respiratory diseases.