Targeted Nanoparticles to Treat Inflammation After Intracerebral Hemorrhage

Developing VCAM-1-targeted lipid nanoparticles delivering IL-10 mRNA to reduce neuroinflammation and improve outcomes after intracerebral hemorrhage.
Completed Other Animal Models Biological & Mechanistic Cytokine Signaling Experimental Platforms & Models Innate Immunity Neuro-Immune Interactions Therapeutic Development Translational & Clinical

Funding Year: 2024

Project Overview

Intracerebral hemorrhage is a lethal form of stroke with no effective therapies, and neuroinflammation plays a central role in secondary brain injury following ICH. This project develops lipid nanoparticles (LNPs) functionalized with vascular cell adhesion molecule-1 (VCAM-1) antibodies to deliver mRNA cargo more efficiently across the blood-brain barrier to activated macrophages in the brain. VCAM-1-targeted LNPs encapsulating IL-10 mRNA significantly reduced lesion volume and improved motor behavior in an ICH mouse model, and were found to preferentially express in infiltrated macrophages — shifting their phenotype toward anti-inflammatory profiles. These findings establish VCAM-LNPs as a clinically promising platform for targeted acute neuroinflammation therapy, with next-generation LNPs incorporating enhanced peripheral phagocytosis evasion under development.

Impact & Innovation

Delivering immune therapy directly to the inflamed brain after stroke.

 

VCAM-1-targeted LNPs achieve significantly higher brain delivery than untargeted nanoparticles and have demonstrated a therapeutic effect in ICH — shifting macrophage phenotype, reducing hematoma, and improving behavior — establishing a translatable platform for acute neuroinflammation.

  • Demonstrates that VCAM-1-targeted IL-10 mRNA delivery reduces lesion volume, improves motor outcomes, and shifts infiltrated macrophage phenotype toward anti-inflammatory profiles in experimental ICH
  • Advances LNP platform development toward next-generation nanoparticles with enhanced evasion of peripheral phagocytosis for improved brain delivery, with multiple pending grants supporting further translation
  • Advances the Consortium’s From Mechanistic Insight to Translation pillar by moving a targeted mRNA delivery mechanism from experimental ICH models toward a clinically available LNP platform with broad applicability across acute brain inflammatory conditions
Research Approach

A framework designed for discovery

This project combines lipid nanoparticle engineering, mRNA delivery, and preclinical ICH modeling to develop and validate VCAM-1-targeted LNPs as a platform for targeted anti-inflammatory therapy after intracerebral hemorrhage. The work moves from nanoparticle functionalization and optimization through in vivo efficacy and mechanistic studies.

Engineering and functionalization of LNPs with VCAM-1-targeting moieties; IL-10 mRNA encapsulation and delivery in experimental ICH mouse models; assessment of brain delivery efficiency, lesion volume, and motor behavior outcomes; macrophage phenotype analysis by histology and serial MRI; and development of next-generation LNPs with enhanced evasion of peripheral phagocytosis for improved brain-targeted delivery.

Experimental ICH mouse model datasets measuring lesion volume, hematoma size, and motor behavior outcomes; brain delivery and mRNA expression datasets comparing VCAM-LNPs to untargeted LNPs; macrophage phenotype datasets tracking shifts from activated to anti-inflammatory profiles; and serial MRI and histology datasets for longitudinal outcome assessment.

Validation of VCAM-1-targeted IL-10 mRNA LNPs as an effective, clinically translatable platform for reducing neuroinflammation and improving outcomes after ICH, with mechanistic investigation of macrophage phenotype shifting and hematoma clearance. Next-generation LNP development and multiple pending grants position this work for rapid advancement toward clinical translation.

Investigators & Institutions

Powering the science

Principal Investigator

Sahily Reyes-Esteves, MD, PhD

Colton Centers & Institutions

Colton Center for Autoimmunity at the University of Pennsylvania

Perelman School of Medicine

Research Outputs

From insight to impact

Publications

Inflammatory mischief managed: how retinoic acid calms heart attacks at the (marrow) source

Science Immunology
Reyes-Esteves, S; Hunter, CA June 2025
Biological & MechanisticCytokine SignalingInnate ImmunityTherapeutic DevelopmentTranslational & ClinicalOtherUniversity of Pennsylvania

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

bioRxiv [Preprint]
Reyes-Esteves, S; Majumder, A; Marzolini, N; Zamora, M; Wang, Y; Espy, C; Papp, TE; Akyianu, A; Nong, J; Messe, L; Omo-Lamai, S; Parhiz, H; Myerson, J; Marcos-Contreras, O; Brenner, J April 2025
Animal ModelsBiological & MechanisticCytokine SignalingExperimental Platforms & ModelsInnate ImmunityTherapeutic DevelopmentTranslational & ClinicalOtherUniversity of Pennsylvania

Additional Outputs

Grants awarded:

  • 2025 Cerebrovascular Research Award from the Aneurysm and AVM Foundation
  • KL2 Mentored Career Development Award 2024–2026.

Grants pending:

  • PhRMA Foundation Faculty Starter Award on Translational Medicine
  • NINDS K08 Clinician Mentored Research Award (June cycle)
  • McCabe Fund Fellow Award 2025
  • RNA Institute AIRFoundry Pilot Grant 2025.

Additional publications in neurology, nanocarrier pharmacokinetics, and palliative care also generated from this project period.