ArticleNature nanotechnology2025
Limiting endosomal damage sensing reduces inflammation triggered by lipid nanoparticle endosomal escape.
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Article in Nature nanotechnology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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44citing papers in PubMed
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Who cites it
44 citing papers in PubMed.
- A dual-targeting mRNA lipid nanoparticle restores ABCA1-dependent cholesterol homeostasis to promote repair of age-related bone defects.Bioactive materials · 2027Article
- Elucidate the structural role of helper lipids in modulating hepatic expression following repeated intravenous administration of mRNA-LNPs.Materials today. Bio · 2026Article
- Comparative analysis of clinically approved lipid nanoparticles for intranasal siRNA delivery against SARS-CoV-2.Drug delivery and translational research · 2026Article
- Bioactive lipid-derived nanoparticles for RNA delivery.Materials today (Kidlington, England) · 2026Article
- Detaching Photosensitive Nanoparticles from Cells Prevents Them from Remaining in Cells after Photoporation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Spatiotemporal control of STING activation and saRNA delivery decouples humoral and cellular immunity.bioRxiv : the preprint server for biology · 2026Article
- Research Advances on Organelle-Targeted Drug Delivery Systems for the Treatment of Brain Tumors and Central Nervous System Inflammation.Pharmaceutics · 2026Review
- Milk-derived extracellular vesicles loaded with miR-146a-5p as a novel therapeutic strategy for allergic airway inflammation.Molecular therapy. Nucleic acids · 2026Article
- Lipid nanoparticles as active biointerfaces: From membrane interaction to systemic dysregulation.Acta pharmaceutica Sinica. B · 2026Review
- Inhalable Degradation-Tunable Hybrid Nanoparticles With Rapid Lysosomal Escape for Dual siRNA Therapy Against NSCLC.Small (Weinheim an der Bergstrasse, Germany) · 2026Article
- Enhancing Lipid Nanoparticle-Mediated Circular RNA and mRNA Expression in the Placenta through Inhibition of IFNAR-JAK-STAT Signaling.Nano letters · 2026Article
- Review
- Lipid Nanoparticles for Gene Therapy: Unresolved Challenges in Manufacturing, Transdermal Delivery, Machine Learning, Endosomal Escape, and the Protein Corona.Pharmaceutics · 2026Review
- Pulmonary Delivery of Self-Amplifying RNA: Balancing Inflammation and Durable Transgene Expression.ACS nano · 2026Article
- Defining Composition-Cytokine Relationships Enables the Design of Lipid Nanoparticles with Programmed Immunogenicity.Small (Weinheim an der Bergstrasse, Germany) · 2026Article
- From Morphology to Mechanism: Cryo-Electron Microscopy Insights into Lipid Nanoparticles for RNA Delivery.ACS nano · 2026Review
- E-selectin and transferrin receptor functionalized synthetic miRNA nanoshuttles with therapeutic potential in stroke.Drug delivery and translational research · 2026Article
- Review
- The RNA delivery dilemma-lipid versus polymer nanoparticle platforms.Drug delivery and translational research · 2026Article
- Decoding Undesirable Inflammatory Responses of Nucleic Acid-Delivering Lipid Nanoparticles.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
Corrections and comments
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Authors and funding
39 authors.
Serena Omo-Lamai *Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0003-3305-4585
Yufei Wang *Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Manthan N Patel *Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Aleksa MilosavljevicDepartment of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0002-0282-034X
Daniel ZuschlagDepartment of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0001-6696-2606
Subhajit PoddarDivision of Rheumatology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0002-9764-3242
Jichuan WuDivision of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0003-0068-5049
Liuqian WangDepartment of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, USA.ORCID http://orcid.org/0009-0003-9017-3449
Fengyi DongDepartment of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, USA.
Carolann EspyDepartment of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Aparajeeta MajumderDivision of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Eno-Obong EssienDivision of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0003-0277-7422
Mengwen ShenEmergency Medical Department, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.ORCID http://orcid.org/0000-0002-1186-5654
Breana ChannerDepartment of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0003-2461-4894
Tyler E PappDivision of Infectious Diseases, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0001-5116-0782
Michael TobinDepartment of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, USA.
Rhea MaheshwariDepartment of Neurosciences, Case Western Reserve University, Cleveland, OH, USA.ORCID http://orcid.org/0009-0009-5973-6104
Sumin JeongDepartment of Bioengineering, George R. Brown School of Engineering, Rice University, Houston, TX, USA.ORCID http://orcid.org/0009-0005-4988-7751
Sofia PatelDepartment of Chemical Engineering, School of Engineering and Applied Sciences, University of Virginia, Charlottesville, VA, USA.
Anit ShahDivision of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0002-6037-7585
Shruthi MuraliDepartment of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0003-0214-0341
Liam S ChaseDepartment of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, USA.
Marco E ZamoraDepartment of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0002-7858-307X
Mariah L ArralDepartment of Chemical Engineering, Carnegie Mellon University, Pittsburgh, PA, USA.
Oscar A Marcos-ContrerasDepartment of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0002-1247-4882
Jacob W MyersonDepartment of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0002-5686-8437
Christopher A HunterDepartment of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Dennis DischerDepartment of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, USA.
Peter J GaskillDepartment of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0003-0095-5424
Andrew TsourkasDepartment of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0001-7758-1753
Vladimir R MuzykantovDepartment of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Igor BrodskyDepartment of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Sunny ShinDepartment of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Kathryn A WhiteheadDepartment of Chemical Engineering, Carnegie Mellon University, Pittsburgh, PA, USA.
Hamideh ParhizDivision of Infectious Diseases, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Jeremy KatzenDivision of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Jonathan J MinerDivision of Rheumatology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Dirk TraunerDepartment of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA.
Jacob S BrennerDepartment of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, USA. Jacob.Brenner@pennmedicine.upenn.edu.ORCID http://orcid.org/0000-0001-8437-0161
Funding
Tumor cell instrinsic DNA damage signaling to the immune responseP01CA265794 · NCI · UNIVERSITY OF PENNSYLVANIA · PI David Michael Chenoweth · 2023 to 2026
$8.5MMechanisms of STING-associated immunodeficiencyR01AI143982 · NIAID · WASHINGTON UNIVERSITY · PI Jonathan J Miner · 2019 to 2026
$4.6MStiff, solid microenvironments induce Chromosome loss and challenge Epigenetic therapiesU01CA254886 · NCI · UNIVERSITY OF PENNSYLVANIA · PI DISCHER, DENNIS E. · 2021 to 2025
$4.3MBenzodiazepine mediated mechanisms of transcriptional semi-quiescence in discrete myeloid populationsR01DA057337 · NIDA · DREXEL UNIVERSITY · PI Peter Jesse Gaskill, Zachary Alan Klase · 2022 to 2026
$3.4MRole of TREX1 in age-related hereditary leukoencephalopathyR01NS131480 · NINDS · UNIVERSITY OF PENNSYLVANIA · PI Jonathan J Miner · 2023 to 2026
$3.2MVascular Targeting of Nanocarriers for RNAR01HL155106 · NHLBI · UNIVERSITY OF PENNSYLVANIA · PI MUZYKANTOV, VLADIMIR R, WEISSMAN, DREW · 2021 to 2024
$3.1MDual drug delivery to lung/blood interface in respiratory infections.R01HL157189 · NHLBI · UNIVERSITY OF PENNSYLVANIA · PI MUZYKANTOV, VLADIMIR R · 2021 to 2024
$2.9MmRNA-LNPs for ARDSR01HL164594 · NHLBI · UNIVERSITY OF PENNSYLVANIA · PI Jacob Brenner, Hamideh Parhiz · 2023 to 2026
$2.7MControlling complement to unleash nanomedicine for acute critical illnessesR01HL160694 · NHLBI · UNIVERSITY OF PENNSYLVANIA · PI BRENNER, JACOB, MUZYKANTOV, VLADIMIR R · 2022 to 2025
$2.7MNanomedicine for ARDS: A new paradigm to target drugs to multiple cell types within alveolar capillariesR01HL153510 · NHLBI · UNIVERSITY OF PENNSYLVANIA · PI BRENNER, JACOB · 2020 to 2024
$2.0MDefining molecular mechanisms by which stimulant evoked dopamine drives inflammation and neuronal dysfunction in neuroHIVR33DA058501 · NIDA · DREXEL UNIVERSITY · PI Peter Jesse Gaskill · 2025 to 2026
$1.4MTargeting the gatekeepers: Bolstering blood-brain barrier function using targeted nanomedicine in acute ischemic strokeR01NS131279 · NINDS · UNIVERSITY OF PENNSYLVANIA · PI Oscar A. Marcos-Contreras · 2024 to 2026
$1.2MAmerican Heart Association (American Heart Association, Inc.) 23PRE1014444American Heart Association (American Heart Association, Inc.) 24PRE1195406NCI NIH HHS P01 CA265794NCI NIH HHS U01 CA254886NHLBI NIH HHS F31 HL154662NHLBI NIH HHS K08 HL150226NHLBI NIH HHS R01 HL153510NHLBI NIH HHS R01 HL155106NHLBI NIH HHS R01 HL157189NHLBI NIH HHS R01 HL160694NHLBI NIH HHS R01 HL164594NIAID NIH HHS F30 AI179472NIAID NIH HHS R01 AI143982NIA NIH HHS F31 AG077874NIDA NIH HHS R01 DA057337NIDA NIH HHS R33 DA058501NIDA NIH HHS R61 DA058501NINDS NIH HHS R01 NS131279NINDS NIH HHS R01 NS131480NINDS NIH HHS R41 NS130812U.S. Department of Health & Human Services | National Institutes of Health (NIH) 1F31AG077874-01U.S. Department of Health & Human Services | National Institutes of Health (NIH) 5K08HL150226U.S. Department of Health & Human Services | National Institutes of Health (NIH) F31HL154662U.S. Department of Health & Human Services | National Institutes of Health (NIH) R41NS130812U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) R01HL164594U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) R01HL60694U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) R01 NS 131279U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse (NIDA) R01DA057337U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse (NIDA) R61DA058501
Abstract
Lipid nanoparticles (LNPs) have emerged as the dominant platform for RNA delivery, but they induce severe inflammation. Here we show that LNPs' hallmark feature, endosomal escape, which is necessary for RNA expression, also triggers inflammation by causing endosomal membrane damage. Large, irreparable, endosomal holes are recognized by cytosolic proteins called galectins, which regulate downstream inflammation. We find that inhibition of galectins abrogates LNP-associated inflammation, both in vitro and in vivo. Moreover, we show that a unique class of ionizable lipids can create smaller endosomal holes, reparable by the endosomal sorting complex required for transport (ESCRT) pathway. Such lipids can produce high expression from cargo messenger RNA with minimal inflammation. Finally, we show that both galectin inhibition or ESCRT-recruiting ionizable lipids allow for treatment of highly inflammatory disease models by therapeutic mRNAs. These strategies should lead to safer non-inflammatory LNPs that can be generally used to treat inflammatory diseases.
Indexed as
EndosomesInflammationLipidsNanoparticlesAnimalsEndosomal Sorting Complexes Required for TransportGalectinsHumansLiposomesMiceRNA, MessengerEndosomal Sorting Complexes Required for TransportGalectinsLipid NanoparticlesLipidsLiposomesRNA, Messenger
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