Proceedings of the National Academy of Sciences,
Год журнала:
2024,
Номер
121(32)
Опубликована: Июль 30, 2024
Monogenic
blood
diseases
are
among
the
most
common
genetic
disorders
worldwide.
These
result
in
significant
pediatric
and
adult
morbidity,
some
can
death
prior
to
birth.
Novel
ex
vivo
hematopoietic
stem
cell
(HSC)
gene
editing
therapies
hold
tremendous
promise
alter
therapeutic
landscape
but
not
without
potential
limitations.
In
offer
a
potentially
safer
more
accessible
treatment
for
these
hindered
by
lack
of
delivery
vectors
targeting
HSCs,
which
reside
difficult-to-access
bone
marrow
niche.
Here,
we
propose
that
this
biological
barrier
be
overcome
taking
advantage
HSC
residence
easily
liver
during
fetal
development.
To
facilitate
cargo
developed
an
ionizable
lipid
nanoparticle
(LNP)
platform
CD45
receptor
on
surface
HSCs.
After
validating
targeted
LNPs
improved
messenger
ribonucleic
acid
(mRNA)
lineage
cells
via
CD45-specific
mechanism
vitro,
demonstrated
mediated
safe,
potent,
long-term
modulation
HSCs
multiple
mouse
models.
We
further
optimized
LNP
vitro
encapsulate
deliver
CRISPR-based
nucleic
cargos.
Finally,
showed
enhanced
at
proof-of-concept
locus
after
single
utero
intravenous
injection.
By
development,
our
Systematically
Targeted
Editing
Machinery
(STEM)
may
provide
translatable
strategy
treat
monogenic
before
Nature Biotechnology,
Год журнала:
2024,
Номер
42(10), С. 1526 - 1537
Опубликована: Янв. 8, 2024
Prime
editing
enables
precise
installation
of
genomic
substitutions,
insertions
and
deletions
in
living
systems.
Efficient
vitro
vivo
delivery
prime
components,
however,
remains
a
challenge.
Here
we
report
editor
engineered
virus-like
particles
(PE-eVLPs)
that
deliver
proteins,
guide
RNAs
nicking
single
as
transient
ribonucleoprotein
complexes.
We
systematically
v3
v3b
PE-eVLPs
with
65-
to
170-fold
higher
efficiency
human
cells
compared
PE-eVLP
construct
based
on
our
previously
reported
base
eVLP
architecture.
In
two
mouse
models
genetic
blindness,
injections
resulted
therapeutically
relevant
levels
the
retina,
protein
expression
restoration
partial
visual
function
rescue.
Optimized
support
ribonucleoproteins,
enhancing
potential
safety
by
reducing
off-target
obviating
possibility
oncogenic
transgene
integration.
Journal of Biomedical Science,
Год журнала:
2023,
Номер
30(1)
Опубликована: Окт. 7, 2023
mRNA-based
drugs
have
tremendous
potential
as
clinical
treatments,
however,
a
major
challenge
in
realizing
this
drug
class
will
promise
to
develop
methods
for
safely
delivering
the
bioactive
agents
with
high
efficiency
and
without
activating
immune
system.
With
regard
mRNA
vaccines,
researchers
modified
structure
enhance
its
stability
promote
systemic
tolerance
of
antigenic
presentation
non-inflammatory
contexts.
Still,
delivery
naked
mRNAs
is
inefficient
results
low
levels
antigen
protein
production.
As
such,
lipid
nanoparticles
been
utilized
improve
protect
cargo
from
extracellular
degradation.
This
advance
was
milestone
development
vaccines
dispelled
skepticism
about
technology
yield
clinically
approved
medicines.
Following
resounding
success
COVID-19,
many
other
proposed
treatment
variety
diseases.
review
begins
discussion
modifications
vehicles,
well
factors
that
influence
administration
routes.
Then,
we
summarize
applications
discuss
further
key
points
pertaining
preclinical
targeting
wide
range
Finally,
latest
market
trends
future
drugs.
Advanced Materials,
Год журнала:
2023,
Номер
unknown
Опубликована: Окт. 4, 2023
Abstract
Lipid‐based
nanoparticles
(LBNPs)
are
currently
the
most
promising
vehicles
for
nucleic
acid
drug
(NAD)
delivery.
Although
their
clinical
applications
have
achieved
success,
NAD
delivery
efficiency
and
safety
still
unsatisfactory,
which
are,
to
a
large
extent,
due
existence
of
multi‐level
physiological
barriers
in
vivo.
It
is
important
elucidate
interactions
between
these
LBNPs,
will
guide
more
rational
design
efficient
with
low
adverse
effects
facilitate
broader
therapeutics.
This
review
describes
obstacles
challenges
biological
at
systemic,
organ,
sub‐organ,
cellular,
subcellular
levels.
The
strategies
overcome
comprehensively
reviewed,
mainly
including
physically/chemically
engineering
LBNPs
directly
modifying
by
auxiliary
treatments.
Then
potentials
successful
translation
preclinical
studies
into
clinic
discussed.
In
end,
forward
look
on
manipulating
protein
corona
(PC)
addressed,
may
pull
off
trick
overcoming
those
significantly
improve
efficacy
LBNP‐based
NADs
Nature Communications,
Год журнала:
2024,
Номер
15(1)
Опубликована: Июль 5, 2024
Abstract
Fully
targeted
mRNA
therapeutics
necessitate
simultaneous
organ-specific
accumulation
and
effective
translation.
Despite
some
progress,
delivery
systems
are
still
unable
to
fully
achieve
this.
Here,
we
reformulate
lipid
nanoparticles
(LNPs)
through
adjustments
in
material
structures
compositions
systematically
the
pulmonary
hepatic
(respectively)
distribution
expression.
A
combinatorial
library
of
degradable-core
based
ionizable
cationic
lipids
is
designed,
following
by
optimisation
LNP
compositions.
Contrary
current
paradigms,
our
findings
demonstrate
that
cholesterol
phospholipid
dispensable
for
functionality.
Specifically,
cholesterol-removal
addresses
persistent
challenge
preventing
nanoparticle
tissues.
By
modulating
simplifying
intrinsic
components,
concurrent
translation
achieved
lung
liver,
respectively.
This
targeting
strategy
applicable
existing
with
potential
expand
progress
precise
therapy
diverse
diseases.
