schliessen

Filtern

 

Bibliotheken

Efficiency of siRNA delivery by lipid nanoparticles is limited by endocytic recycling

Despite efforts to understand the interactions between nanoparticles and cells, the cellular processes that determine the efficiency of intracellular drug delivery remain unclear. Here we examine cellular uptake of short interfering RNA (siRNA) delivered in lipid nanoparticles (LNPs) using cellular... Full description

Journal Title: Nature biotechnology 2013, Vol.31 (7), p.653-658
Main Author: Sahay, Gaurav
Other Authors: Querbes, William , Alabi, Christopher , Eltoukhy, Ahmed , Sarkar, Sovan , Zurenko, Christopher , Karagiannis, Emmanouil , Love, Kevin , Chen, Delai , Zoncu, Roberto , Buganim, Yosef , Schroeder, Avi , Langer, Robert , Anderson, Daniel G
Format: Electronic Article Electronic Article
Language: English
Subjects:
RNA
Publisher: United States: Nature Publishing Group
ID: ISSN: 1087-0156
Link: https://www.ncbi.nlm.nih.gov/pubmed/23792629
Zum Text:
SendSend as email Add to Book BagAdd to Book Bag
Staff View
recordid: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3814166
title: Efficiency of siRNA delivery by lipid nanoparticles is limited by endocytic recycling
format: Article
creator:
  • Sahay, Gaurav
  • Querbes, William
  • Alabi, Christopher
  • Eltoukhy, Ahmed
  • Sarkar, Sovan
  • Zurenko, Christopher
  • Karagiannis, Emmanouil
  • Love, Kevin
  • Chen, Delai
  • Zoncu, Roberto
  • Buganim, Yosef
  • Schroeder, Avi
  • Langer, Robert
  • Anderson, Daniel G
subjects:
  • Biological transport
  • Carrier Proteins
  • Endocytosis
  • Endocytosis - genetics
  • Gene Silencing
  • Gene Transfer Techniques
  • Humans
  • Lipids
  • Lipids - administration & dosage
  • Lipids - chemistry
  • Lipids - genetics
  • Membrane Glycoproteins
  • Metal Nanoparticles - administration & dosage
  • Metal Nanoparticles - chemistry
  • Microscopy, Confocal
  • Nanoparticles
  • Pharmaceutical sciences
  • Ribonucleic acid
  • RNA
  • RNA, Small Interfering - administration & dosage
  • RNA, Small Interfering - chemistry
  • RNA, Small Interfering - genetics
  • Signal Transduction - genetics
  • TOR Serine-Threonine Kinases - genetics
  • TOR Serine-Threonine Kinases - metabolism
ispartof: Nature biotechnology, 2013, Vol.31 (7), p.653-658
description: Despite efforts to understand the interactions between nanoparticles and cells, the cellular processes that determine the efficiency of intracellular drug delivery remain unclear. Here we examine cellular uptake of short interfering RNA (siRNA) delivered in lipid nanoparticles (LNPs) using cellular trafficking probes in combination with automated high-throughput confocal microscopy. We also employed defined perturbations of cellular pathways paired with systems biology approaches to uncover protein-protein and protein-small molecule interactions. We show that multiple cell signaling effectors are required for initial cellular entry of LNPs through macropinocytosis, including proton pumps, mTOR and cathepsins. siRNA delivery is substantially reduced as ≅70% of the internalized siRNA undergoes exocytosis through egress of LNPs from late endosomes/lysosomes. Niemann-Pick type C1 (NPC1) is shown to be an important regulator of the major recycling pathways of LNP-delivered siRNAs. NPC1-deficient cells show enhanced cellular retention of LNPs inside late endosomes and lysosomes, and increased gene silencing of the target gene. Our data suggest that siRNA delivery efficiency might be improved by designing delivery vehicles that can escape the recycling pathways.
language: eng
source:
identifier: ISSN: 1087-0156
fulltext: no_fulltext
issn:
  • 1087-0156
  • 1546-1696
url: Link


@attributes
NO1
SEARCH_ENGINEprimo_central_multiple_fe
SEARCH_ENGINE_TYPEPrimo Central Search Engine
RANK2.7989514
LOCALfalse
PrimoNMBib
record
control
sourceidgale_pubme
recordidTN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3814166
sourceformatXML
sourcesystemPC
galeidA337720578
sourcerecordidA337720578
originalsourceidFETCH-LOGICAL-1619t-9e4fccc969bd09489224e5c80c8659ca553ffd134092737a9818daf6763980550
addsrcrecordideNqNklFrFDEQxxdRbK2Cn0AWfFHwzmR3k01ehKO0WigWqvU1ZLOT7ZS95Nxki_vtm6Pntas-SCAJM7_5ZzIzWfaakiUlpfjomrgsOK2eZIeUVXxBueRP052IekEo4wfZixBuCCG84vx5dlCUtSx4IQ-zqxNr0SA4M-Xe5gEvv67yFnq8hWHKmynvcYNt7rTzGz1END2EHEMyrzFCuyXAtd5MyZUPYCbTo-teZs-s7gO82p1H2dXpyffjL4vzi89nx6vzlCCVcSGhssYYyWXTElkJWRQVMCOIEZxJoxkrrW1pWRFZ1GWtpaCi1ZbXvJSCMEaOsk_3upuxWUNrwMVB92oz4FoPk_Ia1dzj8Fp1_laVglaU8yTwbicw-J8jhKjWGAz0vXbgx6ASVTAqWE0S-vYP9MaPg0vfU7SUMqVIaPFAdboHhc769K7ZiqpVWdZ1QVgtErX8B5VWC2s03oHFZJ8FvJ8FJCbCr9jpMQR19u3y_9mLH3P2wyO2GQM6CGkL2F3HcB8yw3flMoMPYQC7LzUlajuJKk2i2k5iQt88bs0e_D16DzXYaxmMOqLfdgr7vxXvAMOJ5Po
sourcetypeOpen Access Repository
isCDItrue
recordtypearticle
pqid1399092012
display
typearticle
titleEfficiency of siRNA delivery by lipid nanoparticles is limited by endocytic recycling
creatorSahay, Gaurav ; Querbes, William ; Alabi, Christopher ; Eltoukhy, Ahmed ; Sarkar, Sovan ; Zurenko, Christopher ; Karagiannis, Emmanouil ; Love, Kevin ; Chen, Delai ; Zoncu, Roberto ; Buganim, Yosef ; Schroeder, Avi ; Langer, Robert ; Anderson, Daniel G
creatorcontribSahay, Gaurav ; Querbes, William ; Alabi, Christopher ; Eltoukhy, Ahmed ; Sarkar, Sovan ; Zurenko, Christopher ; Karagiannis, Emmanouil ; Love, Kevin ; Chen, Delai ; Zoncu, Roberto ; Buganim, Yosef ; Schroeder, Avi ; Langer, Robert ; Anderson, Daniel G
descriptionDespite efforts to understand the interactions between nanoparticles and cells, the cellular processes that determine the efficiency of intracellular drug delivery remain unclear. Here we examine cellular uptake of short interfering RNA (siRNA) delivered in lipid nanoparticles (LNPs) using cellular trafficking probes in combination with automated high-throughput confocal microscopy. We also employed defined perturbations of cellular pathways paired with systems biology approaches to uncover protein-protein and protein-small molecule interactions. We show that multiple cell signaling effectors are required for initial cellular entry of LNPs through macropinocytosis, including proton pumps, mTOR and cathepsins. siRNA delivery is substantially reduced as ≅70% of the internalized siRNA undergoes exocytosis through egress of LNPs from late endosomes/lysosomes. Niemann-Pick type C1 (NPC1) is shown to be an important regulator of the major recycling pathways of LNP-delivered siRNAs. NPC1-deficient cells show enhanced cellular retention of LNPs inside late endosomes and lysosomes, and increased gene silencing of the target gene. Our data suggest that siRNA delivery efficiency might be improved by designing delivery vehicles that can escape the recycling pathways.
identifier
0ISSN: 1087-0156
1EISSN: 1546-1696
2DOI: 10.1038/nbt.2614
3PMID: 23792629
languageeng
publisherUnited States: Nature Publishing Group
subjectBiological transport ; Carrier Proteins ; Endocytosis ; Endocytosis - genetics ; Gene Silencing ; Gene Transfer Techniques ; Humans ; Lipids ; Lipids - administration & dosage ; Lipids - chemistry ; Lipids - genetics ; Membrane Glycoproteins ; Metal Nanoparticles - administration & dosage ; Metal Nanoparticles - chemistry ; Microscopy, Confocal ; Nanoparticles ; Pharmaceutical sciences ; Ribonucleic acid ; RNA ; RNA, Small Interfering - administration & dosage ; RNA, Small Interfering - chemistry ; RNA, Small Interfering - genetics ; Signal Transduction - genetics ; TOR Serine-Threonine Kinases - genetics ; TOR Serine-Threonine Kinases - metabolism
ispartofNature biotechnology, 2013, Vol.31 (7), p.653-658
rights
0COPYRIGHT 2013 Nature Publishing Group
1Copyright Nature Publishing Group Jul 2013
lds50peer_reviewed
oafree_for_read
citedbyFETCH-LOGICAL-1619t-9e4fccc969bd09489224e5c80c8659ca553ffd134092737a9818daf6763980550
citesFETCH-LOGICAL-1619t-9e4fccc969bd09489224e5c80c8659ca553ffd134092737a9818daf6763980550
links
openurl$$Topenurl_article
thumbnail$$Usyndetics_thumb_exl
backlink$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23792629$$D View this record in MEDLINE/PubMed
search
creatorcontrib
0Sahay, Gaurav
1Querbes, William
2Alabi, Christopher
3Eltoukhy, Ahmed
4Sarkar, Sovan
5Zurenko, Christopher
6Karagiannis, Emmanouil
7Love, Kevin
8Chen, Delai
9Zoncu, Roberto
10Buganim, Yosef
11Schroeder, Avi
12Langer, Robert
13Anderson, Daniel G
title
0Efficiency of siRNA delivery by lipid nanoparticles is limited by endocytic recycling
1Nature biotechnology
addtitleNat Biotechnol
descriptionDespite efforts to understand the interactions between nanoparticles and cells, the cellular processes that determine the efficiency of intracellular drug delivery remain unclear. Here we examine cellular uptake of short interfering RNA (siRNA) delivered in lipid nanoparticles (LNPs) using cellular trafficking probes in combination with automated high-throughput confocal microscopy. We also employed defined perturbations of cellular pathways paired with systems biology approaches to uncover protein-protein and protein-small molecule interactions. We show that multiple cell signaling effectors are required for initial cellular entry of LNPs through macropinocytosis, including proton pumps, mTOR and cathepsins. siRNA delivery is substantially reduced as ≅70% of the internalized siRNA undergoes exocytosis through egress of LNPs from late endosomes/lysosomes. Niemann-Pick type C1 (NPC1) is shown to be an important regulator of the major recycling pathways of LNP-delivered siRNAs. NPC1-deficient cells show enhanced cellular retention of LNPs inside late endosomes and lysosomes, and increased gene silencing of the target gene. Our data suggest that siRNA delivery efficiency might be improved by designing delivery vehicles that can escape the recycling pathways.
subject
0Biological transport
1Carrier Proteins
2Endocytosis
3Endocytosis - genetics
4Gene Silencing
5Gene Transfer Techniques
6Humans
7Lipids
8Lipids - administration & dosage
9Lipids - chemistry
10Lipids - genetics
11Membrane Glycoproteins
12Metal Nanoparticles - administration & dosage
13Metal Nanoparticles - chemistry
14Microscopy, Confocal
15Nanoparticles
16Pharmaceutical sciences
17Ribonucleic acid
18RNA
19RNA, Small Interfering - administration & dosage
20RNA, Small Interfering - chemistry
21RNA, Small Interfering - genetics
22Signal Transduction - genetics
23TOR Serine-Threonine Kinases - genetics
24TOR Serine-Threonine Kinases - metabolism
issn
01087-0156
11546-1696
fulltextfalse
rsrctypearticle
creationdate2013
recordtypearticle
recordideNqNklFrFDEQxxdRbK2Cn0AWfFHwzmR3k01ehKO0WigWqvU1ZLOT7ZS95Nxki_vtm6Pntas-SCAJM7_5ZzIzWfaakiUlpfjomrgsOK2eZIeUVXxBueRP052IekEo4wfZixBuCCG84vx5dlCUtSx4IQ-zqxNr0SA4M-Xe5gEvv67yFnq8hWHKmynvcYNt7rTzGz1END2EHEMyrzFCuyXAtd5MyZUPYCbTo-teZs-s7gO82p1H2dXpyffjL4vzi89nx6vzlCCVcSGhssYYyWXTElkJWRQVMCOIEZxJoxkrrW1pWRFZ1GWtpaCi1ZbXvJSCMEaOsk_3upuxWUNrwMVB92oz4FoPk_Ia1dzj8Fp1_laVglaU8yTwbicw-J8jhKjWGAz0vXbgx6ASVTAqWE0S-vYP9MaPg0vfU7SUMqVIaPFAdboHhc769K7ZiqpVWdZ1QVgtErX8B5VWC2s03oHFZJ8FvJ8FJCbCr9jpMQR19u3y_9mLH3P2wyO2GQM6CGkL2F3HcB8yw3flMoMPYQC7LzUlajuJKk2i2k5iQt88bs0e_D16DzXYaxmMOqLfdgr7vxXvAMOJ5Po
startdate201307
enddate201307
creator
0Sahay, Gaurav
1Querbes, William
2Alabi, Christopher
3Eltoukhy, Ahmed
4Sarkar, Sovan
5Zurenko, Christopher
6Karagiannis, Emmanouil
7Love, Kevin
8Chen, Delai
9Zoncu, Roberto
10Buganim, Yosef
11Schroeder, Avi
12Langer, Robert
13Anderson, Daniel G
generalNature Publishing Group
scope
0CGR
1CUY
2CVF
3ECM
4EIF
5NPM
6AAYXX
7CITATION
83V.
97QO
107QP
117QR
127T7
137TK
147TM
157X7
167XB
1788A
1888E
1988I
208AO
218FD
228FE
238FG
248FH
258FI
268FJ
278FK
288G5
29ABJCF
30ABUWG
31AZQEC
32BBNVY
33BENPR
34BGLVJ
35BHPHI
36C1K
37DWQXO
38FR3
39FYUFA
40GHDGH
41GNUQQ
42GUQSH
43HCIFZ
44K9.
45L6V
46LK8
47M0S
48M1P
49M2O
50M2P
51M7P
52M7S
53MBDVC
54P64
55PADUT
56PQEST
57PQQKQ
58PQUKI
59PRINS
60PTHSS
61Q9U
62RC3
635PM
sort
creationdate201307
titleEfficiency of siRNA delivery by lipid nanoparticles is limited by endocytic recycling
authorSahay, Gaurav ; Querbes, William ; Alabi, Christopher ; Eltoukhy, Ahmed ; Sarkar, Sovan ; Zurenko, Christopher ; Karagiannis, Emmanouil ; Love, Kevin ; Chen, Delai ; Zoncu, Roberto ; Buganim, Yosef ; Schroeder, Avi ; Langer, Robert ; Anderson, Daniel G
facets
frbrtype5
frbrgroupidcdi_FETCH-LOGICAL-1619t-9e4fccc969bd09489224e5c80c8659ca553ffd134092737a9818daf6763980550
rsrctypearticles
prefilterarticles
languageeng
creationdate2013
topic
0Biological transport
1Carrier Proteins
2Endocytosis
3Endocytosis - genetics
4Gene Silencing
5Gene Transfer Techniques
6Humans
7Lipids
8Lipids - administration & dosage
9Lipids - chemistry
10Lipids - genetics
11Membrane Glycoproteins
12Metal Nanoparticles - administration & dosage
13Metal Nanoparticles - chemistry
14Microscopy, Confocal
15Nanoparticles
16Pharmaceutical sciences
17Ribonucleic acid
18RNA
19RNA, Small Interfering - administration & dosage
20RNA, Small Interfering - chemistry
21RNA, Small Interfering - genetics
22Signal Transduction - genetics
23TOR Serine-Threonine Kinases - genetics
24TOR Serine-Threonine Kinases - metabolism
toplevelpeer_reviewed
creatorcontrib
0Sahay, Gaurav
1Querbes, William
2Alabi, Christopher
3Eltoukhy, Ahmed
4Sarkar, Sovan
5Zurenko, Christopher
6Karagiannis, Emmanouil
7Love, Kevin
8Chen, Delai
9Zoncu, Roberto
10Buganim, Yosef
11Schroeder, Avi
12Langer, Robert
13Anderson, Daniel G
collection
0Medline
1MEDLINE
2MEDLINE (Ovid)
3MEDLINE
4MEDLINE
5PubMed
6CrossRef
7ProQuest Central (Corporate)
8Biotechnology Research Abstracts
9Calcium & Calcified Tissue Abstracts
10Chemoreception Abstracts
11Industrial and Applied Microbiology Abstracts (Microbiology A)
12Neurosciences Abstracts
13Nucleic Acids Abstracts
14Health & Medical Collection
15ProQuest Central (purchase pre-March 2016)
16Biology Database (Alumni Edition)
17Medical Database (Alumni Edition)
18Science Database (Alumni Edition)
19ProQuest Pharma Collection
20Technology Research Database
21ProQuest SciTech Collection
22ProQuest Technology Collection
23ProQuest Natural Science Collection
24Hospital Premium Collection
25Hospital Premium Collection (Alumni Edition)
26ProQuest Central (Alumni) (purchase pre-March 2016)
27Research Library (Alumni Edition)
28Materials Science & Engineering Collection
29ProQuest Central (Alumni Edition)
30ProQuest Central Essentials
31Biological Science Collection
32ProQuest Central
33Technology Collection
34Natural Science Collection
35Environmental Sciences and Pollution Management
36ProQuest Central Korea
37Engineering Research Database
38Health Research Premium Collection
39Health Research Premium Collection (Alumni)
40ProQuest Central Student
41Research Library Prep
42SciTech Premium Collection
43ProQuest Health & Medical Complete (Alumni)
44ProQuest Engineering Collection
45ProQuest Biological Science Collection
46Health & Medical Collection (Alumni Edition)
47Medical Database
48Research Library
49Science Database
50Biological Science Database
51Engineering Database
52Research Library (Corporate)
53Biotechnology and BioEngineering Abstracts
54Research Library China
55ProQuest One Academic Eastern Edition
56ProQuest One Academic
57ProQuest One Academic UKI Edition
58ProQuest Central China
59Engineering Collection
60ProQuest Central Basic
61Genetics Abstracts
62PubMed Central (Full Participant titles)
jtitleNature biotechnology
delivery
delcategoryRemote Search Resource
fulltextno_fulltext
addata
au
0Sahay, Gaurav
1Querbes, William
2Alabi, Christopher
3Eltoukhy, Ahmed
4Sarkar, Sovan
5Zurenko, Christopher
6Karagiannis, Emmanouil
7Love, Kevin
8Chen, Delai
9Zoncu, Roberto
10Buganim, Yosef
11Schroeder, Avi
12Langer, Robert
13Anderson, Daniel G
formatjournal
genrearticle
ristypeJOUR
atitleEfficiency of siRNA delivery by lipid nanoparticles is limited by endocytic recycling
jtitleNature biotechnology
addtitleNat Biotechnol
date2013-07
risdate2013
volume31
issue7
spage653
epage658
pages653-658
issn1087-0156
eissn1546-1696
abstractDespite efforts to understand the interactions between nanoparticles and cells, the cellular processes that determine the efficiency of intracellular drug delivery remain unclear. Here we examine cellular uptake of short interfering RNA (siRNA) delivered in lipid nanoparticles (LNPs) using cellular trafficking probes in combination with automated high-throughput confocal microscopy. We also employed defined perturbations of cellular pathways paired with systems biology approaches to uncover protein-protein and protein-small molecule interactions. We show that multiple cell signaling effectors are required for initial cellular entry of LNPs through macropinocytosis, including proton pumps, mTOR and cathepsins. siRNA delivery is substantially reduced as ≅70% of the internalized siRNA undergoes exocytosis through egress of LNPs from late endosomes/lysosomes. Niemann-Pick type C1 (NPC1) is shown to be an important regulator of the major recycling pathways of LNP-delivered siRNAs. NPC1-deficient cells show enhanced cellular retention of LNPs inside late endosomes and lysosomes, and increased gene silencing of the target gene. Our data suggest that siRNA delivery efficiency might be improved by designing delivery vehicles that can escape the recycling pathways.
copUnited States
pubNature Publishing Group
pmid23792629
doi10.1038/nbt.2614
tpages9
oafree_for_read