ACS Nano,
Journal Year:
2022,
Volume and Issue:
16(9), P. 14792 - 14806
Published: Aug. 29, 2022
Despite
lipid
nanoparticles'
(LNPs)
success
in
the
effective
and
safe
delivery
of
mRNA
vaccines,
an
inhalation-based
therapy
for
lung
diseases
remains
challenging.
LNPs
tend
to
disintegrate
due
shear
stress
during
aerosolization,
leading
ineffective
delivery.
Therefore,
need
remain
stable
through
process
nebulization
mucus
penetration,
yet
labile
enough
endosomal
escape.
To
meet
these
opposing
needs,
we
utilized
PEG
enhance
surficial
stability
with
inclusion
a
cholesterol
analog,
β-sitosterol,
improve
Increased
concentrations
enhanced
resistance
while
β-sitosterol
provided
polyhedral
shape,
facilitating
The
optimized
exhibited
uniform
particle
distribution,
morphology,
rapid
mucosal
diffusion
gene
transfection.
Inhaled
led
localized
protein
production
mouse
without
pulmonary
or
systemic
toxicity.
Repeated
administration
sustained
lungs.
Lastly,
encoding
cystic
fibrosis
transmembrane
conductance
regulator
(CFTR)
was
delivered
after
CFTR-deficient
animal
model,
resulting
expression
this
therapeutic
protein.
This
study
demonstrated
rational
design
approach
clinical
translation
inhalable
LNP-based
therapies.
Nature Communications,
Journal Year:
2020,
Volume and Issue:
11(1)
Published: Feb. 20, 2020
Endosomal
sequestration
of
lipid-based
nanoparticles
(LNPs)
remains
a
formidable
barrier
to
delivery.
Herein,
structure-activity
analysis
cholesterol
analogues
reveals
that
incorporation
C-24
alkyl
phytosterols
into
LNPs
(eLNPs)
enhances
gene
transfection
and
the
length
tail,
flexibility
sterol
ring
polarity
due
-OH
group
is
required
maintain
high
transfection.
Cryo-TEM
displays
polyhedral
shape
for
eLNPs
compared
spherical
LNPs,
while
x-ray
scattering
shows
little
disparity
in
internal
structure.
exhibit
higher
cellular
uptake
retention,
potentially
leading
steady
release
from
endosomes
over
time.
3D
single-particle
tracking
enhanced
intracellular
diffusivity
relative
suggesting
eLNP
traffic
productive
pathways
escape.
Our
findings
show
importance
subcellular
transport
carrying
mRNA
emphasize
need
greater
insights
surface
composition
structural
properties
nanoparticles,
their
interactions
which
enable
designs
improve
endosomal
Science Advances,
Journal Year:
2021,
Volume and Issue:
7(9)
Published: Feb. 26, 2021
Ionizable
lipid
nanoparticles
(LNPs)
have
been
widely
used
for
in
vivo
delivery
of
RNA
therapeutics
into
the
liver.
However,
a
main
challenge
remains
to
develop
LNP
formulations
selective
certain
types
liver
cells,
such
as
hepatocytes
and
sinusoidal
endothelial
cells
(LSECs).
Here,
we
report
engineered
LNPs
targeted
LSECs.
The
effects
particle
size
polyethylene
glycol-lipid
content
were
evaluated
hepatocyte-specific
mRNA
by
ApoE-mediated
cellular
uptake
through
low-density
lipoprotein
receptors.
Targeted
LSECs
was
further
investigated
using
active
ligands.
Incorporation
mannose
allowed
LSECs,
while
minimizing
unwanted
hepatocytes.
These
results
demonstrate
that
great
potential
cell
type-specific
other
tissues.
