# Blood-brain barrier-penetrative lipid nanoparticles enable systemic delivery of TRIM11 mRNA to disaggregate Tau in Alzheimer’s disease models

## TL;DR

A new nanoparticle delivery system enables effective brain delivery of mRNA to clear Tau aggregates in Alzheimer's disease models.

## Contribution

A ligand-free lipid nanoparticle is developed for efficient blood-brain barrier crossing and targeted mRNA delivery to neurons.

## Key findings

- PLNPs increase hippocampal mRNA accumulation and neuronal transfection compared to unformulated mRNA.
- TRIM11 mRNA reduces Tau aggregates and neuroinflammation in Alzheimer’s disease mice.
- Prophylactic dosing prevents Tau pathology and preserves cognitive function in young mice.

## Abstract

Hyperphosphorylated Tau aggregates are a central pathological hallmark of Alzheimer’s disease (AD), yet no approved therapy directly targets this process. mRNA therapeutics provide a transient and non-viral option but are limited by the blood-brain barrier (BBB). TRIM11 is an ATP-independent disaggregase that dissolves pathological Tau fibrils and promotes proteasomal clearance. Here, a ligand-free lipid nanoparticle (PLNP) is developed with zwitterionic, acetylcholine-mimetic poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) as a core component and leverages interactions with nAChRs and chTs to enable BBB transcytosis. Systemic PLNP delivery of TRIM11 mRNA yields an 8.1-fold increase in hippocampal accumulation and >30-fold higher neuronal transfection than unformulated mRNA. In 3×Tg-AD mice, PLNP-mTRIM11 reduces P-Ser396- and AT8-positive Tau aggregates, attenuates neuroinflammation, restores synaptic/neuronal integrity, and improves cognition and nest building for ≥3 months. Early prophylactic dosing prevents Tau pathology and preserves cognitive function, supporting PLNP-mTRIM11 for tauopathy therapy.

•PLNPs achieves efficient BBB transcytosis and neuron-targeted mRNA delivery•TRIM11 mRNA enables controllable restoration of Tau disaggregase for Tau clearance•Systemic administration provides therapeutic and prophylactic benefit in AD mice

PLNPs achieves efficient BBB transcytosis and neuron-targeted mRNA delivery

TRIM11 mRNA enables controllable restoration of Tau disaggregase for Tau clearance

Systemic administration provides therapeutic and prophylactic benefit in AD mice

Shi et al. develop a ligand-free, zwitterionic lipid nanoparticle (PLNP) that enables systemic, BBB-penetrant delivery of mRNA with enhanced hippocampal deposition. TRIM11 efficiently reduces pathological Tau aggregates and neuroinflammation and restores cognition in 3×Tg-AD mice, with prophylactic benefit in younger cohorts, supporting PLNP-mTRIM11 as safe and effective for tauopathies.