The potential of nucleic acid therapeutics to treat diseases by targeting specific cells has resulted in its increasing number of uses in clinical settings. However, the major challenge is to deliver bio-macromolecules into target cells and/or subcellular locations of interest ahead in the development of delivery systems. Although, supercharged residues replaced protein 36 + GFP can facilitate itself and cargoes delivery, its efficiency is still limited. Therefore, we combined our recent progress to further improve 36 + GFP based delivery efficiency. We found that the penetration efficacy of 36 + GFP protein was significantly improved by fusion with CPP-Dot1l or treatment with penetration enhancer dimethyl sulfoxide (DMSO)
in vitro
. After safely packaged with plasmid DNA, we found that the efficacy of
in vitro
and
in vivo
transfection mediated by 36 + GFP-Dot1l fusion protein is also significantly improved than 36 + GFP itself. Our findings illustrated that fusion with CPP-Dot1l or incubation with DMSO is an alternative way to synergically promote 36 + GFP mediated plasmid DNA delivery
in vitro
and
in vivo
.
Accumulating evidence indicates that oxidative stress
and inflammation
are involved in the physiopathology of liver fibrogenesis. Nuclear
factor erythroid 2-related factor 2 (Nrf2) is a key transcription
factor, which regulates the expression of redox regulators to establish
cellular redox homeostasis. The Nrf2 modulator can serve as a primary
cellular defense against the cytotoxic effects of oxidative stress.
We designed a chimeric Keap1–Keap1 peptide (KKP1) based on
the proteolysis-targeting chimera technology. The KKP1 peptide not
only can efficiently penetrate into the rat hepatic stellate cell
line (HSC-T6) cells but also can induce Keap1 protein degradation
by the ubiquitination–proteasome degradation pathway, which
releases Nrf2 and promotes the transcriptional activity of the Nrf2/antioxidant
response element pathway. It then activates the protein expression
of the downstream antioxidant factors, the glutamate-cysteine ligase
catalytic subunit and heme oxygenase-1 (HO-1). Finally, Keap1 protein
degradation inhibits the nuclear factor-kappaB inflammatory signal
pathway, the downstream inflammatory factor tumor necrosis factor
alpha, and the interleukin-1beta protein expression and further inhibits
the expression of the fibrosis biomarker gene. The current research
suggests that our designed KKP1 may provide a new avenue for the future
treatment of liver fibrosis.
Organelles
are specialized subunits within a cell membrane that
perform specific roles or functions, and their dysfunction can lead
to a variety of pathophysiologies including developmental defects,
aging, and diseases (cancer, cardiovascular and neurodegenerative
diseases). Recent studies have shown that cell-penetrating peptide
(CPP)-based pharmacological therapies delivered to organelles or even
directly resulting in organelle replacement can restore cell function
and improve or prevent disease. In this review, we summarized the
current developments in the precise delivery of exogenous cargoes
via CPPs at the organelle level, CPP-mediated organelle delivery,
and discuss their feasibility as next-generation targeting strategies
for the diagnosis and treatment of diseases at the organelle level.
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