Evidence map›Paper›PMID 41316820›Full record

ArticleAdvanced materials (Deerfield Beach, Fla.)2026

Potent Liver-Tropic mRNA Lipid Nanoparticles: ApoE-Mediated Delivery Through a Low-Density Lipoprotein Receptor Independent Uptake Mechanism.

Ashish Sarode, Christian Ortiz, Tadeh Derstepanian, Natalia Vargas-Montoya, Priyal Patel, Nikita Khadse, Saikat Manna, Ryan Landis, Joseph Skaleski, Lianne Boeglin and 7 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Advanced materials (Deerfield Beach, Fla.), 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed.

  1. Article
  2. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

17 authors.

Ashish SarodemRNA Center of Excellence, Sanofi, Waltham, MA, 02451, USA.
Christian OrtizmRNA Center of Excellence, Sanofi, Waltham, MA, 02451, USA.
Tadeh DerstepanianmRNA Center of Excellence, Sanofi, Waltham, MA, 02451, USA.
Natalia Vargas-MontoyamRNA Center of Excellence, Sanofi, Waltham, MA, 02451, USA.
Priyal PatelmRNA Center of Excellence, Sanofi, Waltham, MA, 02451, USA.
Nikita KhadsemRNA Center of Excellence, Sanofi, Waltham, MA, 02451, USA.
Saikat MannamRNA Center of Excellence, Sanofi, Waltham, MA, 02451, USA.
Ryan LandismRNA Center of Excellence, Sanofi, Waltham, MA, 02451, USA.
Joseph SkaleskimRNA Center of Excellence, Sanofi, Waltham, MA, 02451, USA.
Lianne BoeglinmRNA Center of Excellence, Sanofi, Waltham, MA, 02451, USA.
Hongfeng DengmRNA Center of Excellence, Sanofi, Waltham, MA, 02451, USA.
Anusha DiasmRNA Center of Excellence, Sanofi, Waltham, MA, 02451, USA.
Hong WangGenomic Medicine Unit, Sanofi, Waltham, MA, 02451, USA.
Debora Barreiros PetropolisGenomic Medicine Unit, Sanofi, Waltham, MA, 02451, USA.
Barak YahalomAlpha Preclinical, 200 Westboro Road, North Grafton, Worcester, MA, 01536, USA.
Shrirang KarvemRNA Center of Excellence, Sanofi, Waltham, MA, 02451, USA.ORCID https://orcid.org/0000-0002-9433-3089
Frank DeRosamRNA Center of Excellence, Sanofi, Waltham, MA, 02451, USA.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

The development of nucleic acid therapeutics using non-viral delivery systems requires efficient payload delivery to target organs for higher potency and tolerability. While lipid nanoparticle (LNP) formulations influence biodistribution, cellular uptake, and therapeutic efficacy, underlying mechanisms remain incompletely understood. This study develops potent mRNA-LNP formulations and investigates determinants of liver tropism using ornithine transcarbamylase (OTC) deficiency as a protein replacement therapy model. Systematic screening of ionizable and helper lipids, optimization of composition and process, and biophysical characterization identify a liver-tropic helper lipid-1,2-dierucoyl-sn-glycero-3-phosphoethanolamine (DEPE) that modulates LNP structure and apolipoprotein E (ApoE) binding, enhancing liver-specific delivery. Analysis of ionizable lipid chemistry reveals its role in cellular uptake mechanisms, leading to the identification of a novel ionizable lipid designed with N-(2-Hydroxyethyl)piperazine-N'-(4-butanesulfonic acid) (HEPBS) core that enables efficient delivery independent of the low-density lipoprotein receptor (LDLR) pathway. The optimized formulation achieves robust dose responsiveness, sustained therapeutic expression, and favorable tolerability in preclinical models. Therapeutic levels of OTC protein expression are observed with minimal toxicity, as indicated by stable liver function markers and cytokine levels. These findings provide mechanistic insights and establish a platform for mRNA-based protein replacement therapies, supporting broader applications in rare genetic diseases requiring hepatic gene expression.

Indexed as

Apolipoproteins ELipidsLiverNanoparticlesReceptors, LDLRNA, MessengerAnimalsHumansMiceApolipoproteins ELipidsReceptors, LDLRNA, MessengerApoEgene therapyhelper lipidLDLRlipid nanoparticleliver tropismmRNA

Identifiers

PMID41316820
PMCPMC13088227

What OpenQuestion holds

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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.