Journal of controlled release : official journal of the Controlled Release SocietyJun 15, 2026

Lipid nanoparticles using one molecule to deliver therapeutic mRNA to brain tumors across the blood-brain barrier

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 16, 2026

Abstract

Mannose-cholesterol LNPs achieve 9.9-fold greater brain accumulation than non-targeted formulations in healthy mice.

GLUT1 is a potential target for delivering mRNA to brain tumors due to its abundance on brain blood vessels and overexpression in glioblastoma.
High ligand densities on LNPs are necessary for effective GLUT1 engagement but are difficult to achieve with conventional methods.
Mannose-cholesterol conjugation allows for ~30 mol% surface ligand density without compromising mRNA encapsulation.
Functional delivery of Cre mRNA using MC_LNPs shows expression in neurons and astrocytes in Ai14 reporter mice.
In glioblastoma models, mRNA-loaded MC_LNPs reduce tumor burden by 6-fold and extend median survival from 33 to 49 days.

Simplified

Lipid nanoparticle (LNP)-mediated mRNA delivery to brain tumors is limited by the blood-brain barrier (BBB) and lack of active tumor targeting. Glucose transporter 1 (GLUT1), abundant on brain endothelium and overexpressed in glioblastoma, offers a single target for both BBB transcytosis and preferential tumor uptake. However, effective GLUT1 engagement requires high ligand densities on LNPs to compete with blood glucose, a threshold unattainable through conventional PEG-lipid functionalization. Furthermore, incorporating hydrophilic sugar ligands (e.g., glucose, mannose) can disrupt LNP architecture and mRNA encapsulation. Here, mannose-cholesterol LNPs (MC_LNPs) are developed to target GLUT1 and overcome these challenges. Mannose-cholesterol conjugation achieves ∼30 mol% surface ligand density, and incorporating positively charged DC-cholesterol restores >90% mRNA encapsulation. In healthy mice, MC_LNPs achieve 9.9-fold greater brain accumulation than non-targeted formulations, confirming BBB penetration. Functional delivery is validated using Cre mRNA in Ai14 reporter mice, revealing expression in neurons and astrocytes. In orthotopic glioblastoma models, phosphatase and tensin homolog (PTEN) mRNA-loaded MC_LNPs exhibit preferential tumor accumulation, restoring tumor suppression, reducing tumor burden 6-fold, and extending median survival from 33 to 49 days. MC-LNPs represent the first dual-targeted mRNA platform for brain tumors, establishing cholesterol-based functionalization as a strategy to achieve high ligand densities for efficient transporter/receptor targeting.

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Lipid nanoparticles using one molecule to deliver therapeutic mRNA to brain tumors across the blood-brain barrier

Abstract

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