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<p>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.</p>

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Limiting endosomal damage sensing reduces inflammation triggered by lipid nanoparticle endosomal escape

  • 期刊论文

  • 发表日期：

    2025年8月11日

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  • Serena Omo-Lamai,
  • Yufei Wang,
  • Manthan N. Patel,
  • Aleksa Milosavljevic,
  • Daniel Zuschlag,
  • Subhajit Poddar,
  • Jichuan Wu,
  • Liuqian Wang,
  • Fengyi Dong,
  • Carolann Espy,
  • Aparajeeta Majumder,
  • Eno-Obong Essien,
  • Mengwen Shen,
  • Breana Channer,
  • Tyler E. Papp,
  • Michael Tobin,
  • Rhea Maheshwari,
  • Sumin Jeong,
  • Sofia Patel,
  • Anit Shah,
  • Shruthi Murali,
  • Liam S. Chase,
  • Marco E. Zamora,
  • Mariah L. Arral,
  • Oscar A. Marcos-Contreras,
  • Jacob W. Myerson,
  • Christopher A. Hunter,
  • Dennis Discher,
  • Peter J. Gaskill,
  • Andrew Tsourkas,
  • Vladimir R. Muzykantov,
  • Igor Brodsky,
  • Sunny Shin,
  • Kathryn A. Whitehead,
  • Hamideh Parhiz,
  • Jeremy Katzen,
  • Jonathan J. Miner,
  • Dirk Trauner,
  • Jacob S. Brenner

摘要

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.