Abstract
Over
the
two
decades,
RNA
drugs
have
gradually
made
their
way
from
bench
to
bed.
Initially,
was
not
an
ideal
drug
since
molecules
degrade
easily
and
a
relatively
short
half‐life
in
circulation
system.
Nevertheless,
chemical
modification
extended
of
recent
years,
which
makes
new
star
discovery
industry.
hold
many
properties
that
facilitate
application
as
therapeutic
drugs.
RNAs
could
fold
form
complex
conformations
bind
proteins,
small
molecules,
or
other
nucleic
acids,
some
even
catalytic
centers.
Protein‐encoding
are
carriers
genetic
information
DNA
ribosomes,
various
types
non‐coding
cooperate
transcription
translation
through
mechanisms.
To
date,
three
mainstream
therapies
drawn
widespread
attention:
(1)
messenger
encodes
proteins
vaccine
antigens;
(2)
interfering
RNA,
microRNA
(miRNA),
antisense
oligonucleotides
inhibit
activity
pathogenic
RNAs;
(3)
aptamers
regulate
protein
activity.
Here,
we
summarized
current
research
perspectives
therapies,
may
provide
innovative
highlights
for
cancer
therapy.
Journal of Controlled Release,
Год журнала:
2024,
Номер
367, С. 385 - 401
Опубликована: Фев. 1, 2024
The
availability
of
analytical
methods
for
the
characterization
lipid
nanoparticles
(LNPs)
in-vivo
intracellular
delivery
nucleic
acids
is
critical
fast
development
innovative
RNA
therapies.
In
this
study,
protocols
to
measure
(i)
chemical
composition,
(ii)
drug
loading,
(iii)
particle
size,
concentration,
and
stability
as
well
(iv)
structure
morphology
were
evaluated
compared
based
on
a
comprehensive
strategy
linking
key
physical
properties
in-vitro
efficacy
toxicity.
Furthermore,
measurement
assessed
either
by
testing
reproducibility
robustness
same
technique
in
different
laboratories,
or
correlative
approach,
comparing
results
attribute
with
orthogonal
techniques.
measurements
described
here
will
have
an
important
role
during
formulation
determining
robust
quality
attributes
ultimately
supporting
assessment
these
therapeutics.
Proceedings of the National Academy of Sciences,
Год журнала:
2024,
Номер
121(11)
Опубликована: Март 4, 2024
Lipid
nanoparticles
(LNPs)
largely
rely
on
ionizable
lipids
to
yield
successful
nucleic
acid
delivery
via
electrostatic
disruption
of
the
endosomal
membrane.
Here,
we
report
identification
and
evaluation
containing
a
thiophene
moiety
(Thio-lipids).
The
Thio-lipids
can
be
readily
synthesized
Gewald
reaction,
allowing
for
modular
lipid
design
with
functional
constituents
at
various
positions
ring.
Through
rational
structure,
prepared
47
identified
some
structural
criteria
required
in
efficient
mRNA
(messenger
RNA)
encapsulation
vitro
vivo.
Notably,
none
tested
have
pH-response
profile
like
traditional
lipids,
potentially
due
electron
delocalization
core.
Placement
tails
localization
headgroup
core
endow
capability
reach
tissues.
Using
high-throughput
formulation
barcoding
techniques,
optimized
formulations
select
two
top
lipids—
20b
29d
—and
investigated
their
biodistribution
mice.
enabled
LNPs
transfect
liver
spleen,
LNP
transfected
lung
spleen.
Unexpectedly,
was
especially
potent
retina
no
acute
toxicity,
leading
photoreceptors
retinal
pigment
epithelium
non-human
primates.
ACS Nano,
Год журнала:
2024,
Номер
18(2), С. 1464 - 1476
Опубликована: Янв. 4, 2024
The
mRNA
technology
has
emerged
as
a
rapid
modality
to
develop
vaccines
during
pandemic
situations
with
the
potential
protect
against
endemic
diseases.
success
of
in
producing
an
antigen
is
dependent
on
ability
deliver
cells
using
vehicle,
which
typically
consists
lipid
nanoparticle
(LNP).
Self-amplifying
(SAM)
synthetic
platform
that,
besides
encoding
for
interest,
includes
replication
machinery
amplification
cells.
Thus,
SAM
can
generate
many
copies
and
prolong
expression
lower
doses
than
those
required
conventional
mRNA.
This
work
describes
morphology
LNPs
containing
encapsulated
(SAM
LNPs),
being
three
four
times
larger
We
show
evidence
that
changes
its
conformational
structure
when
LNPs,
becoming
more
compact
free
form.
A
characteristic
"bleb"
observed
lipid-rich
core
aqueous
RNA-rich
core,
both
surrounded
by
DSPC-rich
shell.
used
SANS
SAXS
data
confirm
prevalent
LNP
two-core
compartments
where
components
are
heterogeneously
distributed
between
two
cores
capped
cylinder
core–shell
model
interior
was
built
capture
overall
LNP.
These
findings
provide
bleb
two-compartment
structures
be
representative
highlight
need
additional
studies
elucidate
role
spherical
morphologies,
their
mechanisms
formation,
parameters
lead
particular
rational
design
delivery.
Proceedings of the National Academy of Sciences,
Год журнала:
2024,
Номер
121(2)
Опубликована: Янв. 4, 2024
The
ionizable-lipid
component
of
RNA-containing
nanoparticles
controls
the
pH-dependent
behavior
necessary
for
an
efficient
delivery
cargo—the
so-called
endosomal
escape.
However,
it
is
still
empirical
exercise
to
identify
optimally
performing
lipids.
Here,
we
study
two
well-known
ionizable
lipids,
DLin-MC3-DMA
and
DLin-DMA
using
a
combination
experiments,
multiscale
computer
simulations,
electrostatic
theory.
All-atom
molecular
dynamics
experimentally
measured
polar
headgroup
p
K
values,
are
used
develop
coarse-grained
representation
which
enables
investigation
lipid
(LNPs)
through
Monte
Carlo
in
absence
presence
RNA
molecules.
Our
results
show
that
charge
state
lipids
determined
by
interplay
between
shape
chemistry,
providing
explanation
similar
ionization
observed
with
values
about
one-pH-unit
apart.
pH
dependence
significantly
influenced
RNA,
whereby
neutrality
achieved
imparting
finite
constant
per
at
intermediate
values.
simulation
supported
measurements
α-carbon
13
C-NMR
chemical
shifts
eGFP
mRNA
LNPs
both
various
conditions.
Further,
evaluate
applicability
mean-field
Poisson–Boltzmann
theory
capture
these
phenomena.
Abstract
Over
the
two
decades,
RNA
drugs
have
gradually
made
their
way
from
bench
to
bed.
Initially,
was
not
an
ideal
drug
since
molecules
degrade
easily
and
a
relatively
short
half‐life
in
circulation
system.
Nevertheless,
chemical
modification
extended
of
recent
years,
which
makes
new
star
discovery
industry.
hold
many
properties
that
facilitate
application
as
therapeutic
drugs.
RNAs
could
fold
form
complex
conformations
bind
proteins,
small
molecules,
or
other
nucleic
acids,
some
even
catalytic
centers.
Protein‐encoding
are
carriers
genetic
information
DNA
ribosomes,
various
types
non‐coding
cooperate
transcription
translation
through
mechanisms.
To
date,
three
mainstream
therapies
drawn
widespread
attention:
(1)
messenger
encodes
proteins
vaccine
antigens;
(2)
interfering
RNA,
microRNA
(miRNA),
antisense
oligonucleotides
inhibit
activity
pathogenic
RNAs;
(3)
aptamers
regulate
protein
activity.
Here,
we
summarized
current
research
perspectives
therapies,
may
provide
innovative
highlights
for
cancer
therapy.