Nature,
Год журнала:
2024,
Номер
627(8003), С. 416 - 423
Опубликована: Фев. 28, 2024
Abstract
Permanent
epigenetic
silencing
using
programmable
editors
equipped
with
transcriptional
repressors
holds
great
promise
for
the
treatment
of
human
diseases
1–3
.
However,
to
unlock
its
full
therapeutic
potential,
an
experimental
confirmation
durable
after
delivery
transient
in
vivo
is
needed.
To
this
end,
here
we
targeted
Pcsk9
,
a
gene
expressed
hepatocytes
that
involved
cholesterol
homeostasis.
In
vitro
screening
different
editor
designs
indicated
zinc-finger
proteins
were
best-performing
DNA-binding
platform
efficient
mouse
A
single
administration
lipid
nanoparticles
loaded
editors’
mRNAs
almost
halved
circulating
levels
PCSK9
nearly
one
year
mice.
Notably,
and
accompanying
repressive
marks
also
persisted
forced
liver
regeneration,
further
corroborating
heritability
newly
installed
state.
Improvements
construct
design
resulted
development
all-in-one
configuration
term
evolved
engineered
repressor
(EvoETR).
This
design,
which
characterized
by
high
specificity
profile,
reduced
mice
efficiency
comparable
obtained
through
conventional
editing,
but
without
causing
DNA
breaks.
Our
study
lays
foundation
therapeutics
are
based
on
silencing.
Cell,
Год журнала:
2022,
Номер
185(15), С. 2806 - 2827
Опубликована: Июль 1, 2022
In
vivo
gene
editing
therapies
offer
the
potential
to
treat
root
causes
of
many
genetic
diseases.
Realizing
promise
therapeutic
in
requires
ability
safely
and
efficiently
deliver
agents
relevant
organs
tissues
vivo.
Here,
we
review
current
delivery
technologies
that
have
been
used
enable
editing,
including
viral
vectors,
lipid
nanoparticles,
virus-like
particles.
Since
no
single
modality
is
likely
be
appropriate
for
every
possible
application,
compare
benefits
drawbacks
each
method
highlight
opportunities
future
improvements.
Signal Transduction and Targeted Therapy,
Год журнала:
2023,
Номер
8(1)
Опубликована: Март 15, 2023
Exosome
is
a
subgroup
of
extracellular
vesicles,
which
has
been
serving
as
an
efficient
therapeutic
tool
for
various
diseases.
Engineered
exosomes
are
the
sort
modified
with
surface
decoration
and
internal
molecules.
After
appropriate
modification,
engineered
able
to
deliver
antitumor
drugs
tumor
sites
efficiently
precisely
fewer
treatment-related
adverse
effects.
However,
there
still
exist
many
challenges
clinical
translation
exosomes.
For
instance,
what
sources
modification
strategies
could
endow
most
activity
poorly
understood.
Additionally,
how
choose
appropriately
in
different
therapies
another
unresolved
problem.
In
this
review,
we
summarized
characteristics
exosomes,
especially
spatial
temporal
properties.
concluded
recent
advances
cancer
fields,
including
sources,
isolation
technologies,
strategies,
labeling
imaging
methods
Furthermore,
applications
were
summarized,
such
photodynamic
therapy,
gene
immunotherapy.
Consequently,
above
provides
researchers
community
latest
ideas
on
exosome
new
direction
drug
development,
prospective
accelerate
cancer-targeted
therapy.
Journal of the American Chemical Society,
Год журнала:
2022,
Номер
144(21), С. 9184 - 9205
Опубликована: Май 10, 2022
An
inconvenient
hurdle
in
the
practice
of
nanomedicine
is
protein
corona,
a
spontaneous
collection
biomolecular
species
by
nanoparticles
living
systems.
The
corona
dynamic
composition
and
may
entail
improved
water
suspendability
compromised
delivery
targeting
to
nanoparticles.
How
much
this
nonspecific
ensemble
determined
chemistry
nanoparticle
core
its
surface
functionalization,
how
entity
dictated
biological
environments
that
vary
spatiotemporally
vivo?
do
we
"live
with"
exploit
without
significantly
sacrificing
efficacy
nanomedicines
diagnosing
curing
human
diseases?
This
article
discusses
chemical
biophysical
signatures
ponders
challenges
ahead
for
field
nanomedicine.
Advanced Materials,
Год журнала:
2023,
Номер
35(51)
Опубликована: Май 17, 2023
Abstract
Messenger
RNA
(mRNA)
has
received
great
attention
in
the
prevention
and
treatment
of
various
diseases
due
to
success
coronavirus
disease
2019
(COVID‐19)
mRNA
vaccines
(Comirnaty
Spikevax).
To
meet
therapeutic
purpose,
it
is
required
that
must
enter
target
cells
express
sufficient
proteins.
Therefore,
development
effective
delivery
systems
necessary
crucial.
Lipid
nanoparticle
(LNP)
represents
a
remarkable
vehicle
indeed
accelerated
applications
humans,
as
several
mRNA‐based
therapies
have
already
been
approved
or
are
clinical
trials.
In
this
review,
focus
on
mRNA‐LNP‐mediated
anticancer
therapy.
It
summarizes
main
strategies
mRNA‐LNP
formulations,
discusses
representative
approaches
cancer,
points
out
current
challenges
possible
future
directions
research
field.
hoped
these
delivered
messages
can
help
further
improve
application
technology
cancer
Journal of Pharmacology and Experimental Therapeutics,
Год журнала:
2022,
Номер
384(1), С. 133 - 154
Опубликована: Июнь 9, 2022
RNA
interference
(RNAi)
provides
researchers
with
a
versatile
means
to
modulate
target
gene
expression.
The
major
forms
of
RNAi
molecules,
genome-derived
microRNAs
(miRNAs)
and
exogenous
small
interfering
RNAs
(siRNAs),
converge
into
RNA-induced
silencing
complexes
achieve
posttranscriptional
regulation.
has
proven
be
an
adaptable
powerful
therapeutic
strategy
where
advancements
in
chemistry
pharmaceutics
continue
bring
RNAi-based
drugs
the
clinic.
With
four
siRNA
medications
already
approved
by
US
Food
Drug
Administration
(FDA),
several
therapeutics
advance
clinical
trials
functions
that
closely
resemble
their
endogenous
counterparts.
Although
intended
enhance
stability
improve
efficacy,
chemical
modifications
may
increase
risk
off-target
effects
altering
structure,
folding,
biologic
activity
away
from
natural
equivalents.
Novel
technologies
development
today
seek
use
intact
cells
yield
true
agents
better
represent
structures,
stabilities,
activities,
safety
profiles
molecules.
In
this
review,
we
provide
examination
mechanisms
action
miRNAs
siRNAs,
physiologic
pharmacokinetic
barriers
delivery,
summary
delivery
platforms
use.
We
overview
pharmacology
FDA-approved
(patisiran,
givosiran,
lumasiran,
inclisiran)
as
well
five
siRNAs
miRNA-based
currently
trials.
Furthermore,
discuss
direct
expression
stable
carrier-based,
vivo
production
novel
for
research
development.
SIGNIFICANCE
STATEMENT:
our
summarize
concepts
(RNAi),
molecular
mechanisms,
current
state
challenges
drug
focus
discussion
on
Administration-approved
those
entered
investigations.
approaches
producing
new
biological
molecules
are
highlighted.
ACS Nano,
Год журнала:
2023,
Номер
17(23), С. 23223 - 23261
Опубликована: Дек. 2, 2023
Stimuli-responsive
polymers
can
respond
to
internal
stimuli,
such
as
reactive
oxygen
species
(ROS),
glutathione
(GSH),
and
pH,
biological
enzymes,
external
lasers
ultrasound,
etc.,
by
changing
their
hydrophobicity/hydrophilicity,
degradability,
ionizability,
thus
have
been
widely
used
in
biomedical
applications.
Due
the
characteristics
of
tumor
microenvironment
(TME),
stimuli-responsive
that
cater
specifically
TME
extensively
prepare
smart
nanovehicles
for
targeted
delivery
therapeutic
diagnostic
agents
tissues.
Compared
conventional
drug
nanosystems,
TME-responsive
nanosystems
many
advantages,
high
sensitivity,
broad
applicability
among
different
tumors,
functional
versatility,
improved
biosafety.
In
recent
years,
a
great
deal
research
has
devoted
engineering
efficient
polymeric
significant
improvement
made
both
cancer
diagnosis
therapy.
this
review,
we
summarize
some
advances
involving
use
polymer
nanocarriers
delivery,
imaging,
therapy,
theranostics.
Various
chemical
stimuli
will
be
described
context
nanosystems.
Accordingly,
groups
responsible
responsiveness
strategies
incorporate
these
into
discussed
detail.
With
on
topic
expending
at
fast
pace,
innovative
concepts,
sequential
cascade
release,
NIR-II
multifunctional
formulations,
emerged
popular
enhanced
performance,
which
also
included
here
with
up-to-date
illustrations.
We
hope
review
offer
valuable
insights
selection
optimization
help
accelerate
future
applications
treatment.
Nature Communications,
Год журнала:
2022,
Номер
13(1)
Опубликована: Авг. 15, 2022
Abstract
In
humans,
lipid
nanoparticles
(LNPs)
have
safely
delivered
therapeutic
RNA
to
hepatocytes
after
systemic
administration
and
antigen-presenting
cells
intramuscular
injection.
However,
delivery
non-hepatocytes
remains
challenging,
especially
without
targeting
ligands
such
as
antibodies,
peptides,
or
aptamers.
Here
we
report
that
piperazine-containing
ionizable
lipids
(Pi-Lipids)
preferentially
deliver
mRNA
immune
in
vivo
ligands.
After
synthesizing
characterizing
Pi-Lipids,
use
high-throughput
DNA
barcoding
quantify
how
65
chemically
distinct
LNPs
functionally
(i.e.,
translated
into
functional,
gene-editing
protein)
14
cell
types
directly
vivo.
By
analyzing
the
relationships
between
structure
cellular
targeting,
identify
traits
increase
addition,
characterize
Pi-A10,
an
LNP
delivers
liver
splenic
at
clinically
relevant
dose
of
0.3
mg/kg.
These
data
demonstrate
studies
can
with
natural
non-hepatocyte
tropism
support
hypothesis
bioactive
small-molecule
motifs
