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<p>Intracerebral hemorrhage (ICH) is a lethal and highly morbid form of stroke for which there is no disease-specific therapy. Inflammation after ICH is an important mechanism of secondary damage, and the inflamed endothelium in ICH is a promising therapeutic target as it is the gateway for recruitment of peripheral inflammatory cells to the brain. Systemic therapies that target inflammation have been unsuccessful in stroke, in part due to side effects or poor brain delivery. We hypothesized that targeting mRNA encoding IL-10, a potent anti-inflammatory cytokine, to the brain vasculature would improve outcomes in an experimental mouse model of ICH. We manufactured lipid nanoparticles (LNPs) using microfluidics, packaged them with IL-10 mRNA, and conjugated them with antibodies against vascular cellular adhesion molecule (VCAM), which can bind the inflamed brain endothelium after ICH. VCAM LNPs distributed to the brain ~ 4x more than nonspecific LNPs and expressed their cargo in the brain at 10x higher levels. Treatment with VCAM-LNPs containing IL-10 mRNA led to ~ 69% reduction in hematoma size at 72&#xa0;h by histology and decreased lesion size in MRI, and ~ 65% improvement in motor behavior in our model. Finally, we propose that VCAM-IL10-LNPs enact their therapeutic benefit via modulation of brain macrophage phenotype. Our data bring forth a promising therapeutic and delivery strategy for ICH, and shed light on the effects of acute targeting of inflammation in ICH lesion size and behavior. Future experiments will seek to understand how serial dosing affects LNP expression in our model and whether treatment at later time points after ICH can still confer therapeutic effects.</p>

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Targeted lipid nanoparticles containing IL-10 mRNA improve outcomes in experimental intracerebral hemorrhage

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月14日

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  • Sahily Reyes-Esteves,
  • Aparajeeta Majumder,
  • Nicolas Marzolini,
  • Marco E. Zamora,
  • Soomin Jeong,
  • Yufei Wang,
  • Manthan N. Patel,
  • Carolann Espy,
  • Tyler Ellis Papp,
  • Awurama Akyianu,
  • Jia Nong,
  • Lawson Messe,
  • Serena Omo-Lamai,
  • Hamideh Parhiz,
  • Jacob W. Myerson,
  • Oscar A. Marcos-Contreras,
  • Jacob S. Brenner

摘要

Intracerebral hemorrhage (ICH) is a lethal and highly morbid form of stroke for which there is no disease-specific therapy. Inflammation after ICH is an important mechanism of secondary damage, and the inflamed endothelium in ICH is a promising therapeutic target as it is the gateway for recruitment of peripheral inflammatory cells to the brain. Systemic therapies that target inflammation have been unsuccessful in stroke, in part due to side effects or poor brain delivery. We hypothesized that targeting mRNA encoding IL-10, a potent anti-inflammatory cytokine, to the brain vasculature would improve outcomes in an experimental mouse model of ICH. We manufactured lipid nanoparticles (LNPs) using microfluidics, packaged them with IL-10 mRNA, and conjugated them with antibodies against vascular cellular adhesion molecule (VCAM), which can bind the inflamed brain endothelium after ICH. VCAM LNPs distributed to the brain ~ 4x more than nonspecific LNPs and expressed their cargo in the brain at 10x higher levels. Treatment with VCAM-LNPs containing IL-10 mRNA led to ~ 69% reduction in hematoma size at 72 h by histology and decreased lesion size in MRI, and ~ 65% improvement in motor behavior in our model. Finally, we propose that VCAM-IL10-LNPs enact their therapeutic benefit via modulation of brain macrophage phenotype. Our data bring forth a promising therapeutic and delivery strategy for ICH, and shed light on the effects of acute targeting of inflammation in ICH lesion size and behavior. Future experiments will seek to understand how serial dosing affects LNP expression in our model and whether treatment at later time points after ICH can still confer therapeutic effects.