Microglia polarization
plays an important role in poststroke recovery.
Inhibition of proinflammatory (M1) polarization and promotion of anti-inflammatory
(M2) polarization of microglia are potential therapeutic strategies
for inflammation reduction and neuronal recovery after stroke. Here,
we evaluated the central nervous system (CNS)-targeted
short interfering RNA (siRNA) delivery ability of functionalized curdlan
nanoparticles (CMI) and investigated the nuclear factor-κB (NF-κB)
p65 silencing efficiency of CMI-mediated siRNA in microglia, as well
as the resulting neuroprotective effect of microglia polarization
and neuroprotection in vitro and in vivo. The systemic delivery of
NF-κB p65 siRNA (sip65) complexed to CMI nanoparticles in the
mouse model of transient middle cerebral artery occlusion (tMCAO)
resulted in the distribution of siRNA in microglia and significant
silencing in NF-κB p65 in the peri-infarct region. Knockdown
of NF-κB p65 resulted in M1 to M2 phenotypic transition of microglia,
evidenced by the change in the expression pattern of signature cytokines
as well as inducible nitric oxide synthase and CD206. Moreover, the
CMI-mediated silencing of p65 increased the density of neurons and
decreased pyknosis and edema in the peri-infarct region. Assessment
of the neurological deficit score on the Bederson scale revealed a
significantly reduced score in the mouse model of tMCAO treated with
the sip65/CMI complex. Collectively, our data suggest that CMI nanoparticles
are a promising CNS-targeting siRNA delivery system, and NF-κB
p65 may be a potential therapeutic target for inflammation reduction
and poststroke recovery.
Ischemic stroke activates toll-like receptor 4 (TLR4) signaling, resulting in proinflammatory polarization of microglia and secondary neuronal damage. Herein, we report a novel lipid-nanoparticle (LNP)-mediated knockdown of TLR4 in microglia and amelioration of neuroinflammation in a mouse model of transient middle cerebral artery occlusion (tMCAO). siRNA against TLR4 (siTLR4) complexed to the novel LNP (siTLR4/DoGo310), which was based on a dioleoyl-conjugated short peptidomimetic (denote DoGo310), was readily internalized by the oxygen–glucose-deprived (OGD) mouse primary microglia, knocked-down TLR4, and polarized the cell to the anti-inflammatory phenotype in vitro. Systemic administration of siTLR4/DoGo310 LNPs in the tMCAO mice model resulted in the accumulation of siRNA mainly in the Iba1 positive cells in the peri-infarct. Analysis of the peri-infarct brain tissue revealed that a single injection of siTLR4/DoGo310 LNPs led to significant knockdown of TLR4 gene expression, reversing the pattern of cytokines expression, and improving the neurological functions in tMCAO model mice. Our data demonstrate that DoGo310 LNPs could be a promising nanocarrier for CNS-targeted siRNA delivery for the treatment of CNS disorders.
Sugars containing cationic polymers are potential carriers for in vitro and in vivo nucleic acid delivery. Monosaccharides such as glucose and galactose have been chemically conjugated to various materials of synergistic poly-lysine dendrimer systems for efficient and biocompatible delivery of short interfering RNA (siRNA). The synergistic dendrimers, which contain lipid conjugated glucose terminalized lysine dendrimers, have significantly lower adverse impact on cells while maintaining efficient cellular entry. Moreover, the synergistic dendrimers complexed to siRNA induced RNA interference (RNAi) in the cells and profoundly knocked down green fluorescence protein (GFP) as well as the endogenously expressing disease related gene Plk1. The new synergic dendrimers may be promising system for biocompatible and efficient siRNA delivery.
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