Telomerase mRNA-Lipid nanoparticles attenuate neuroinflammation after traumatic brain injury in mice.

Jan 9, 2026bioRxiv : the preprint server for biology

Lipid nanoparticles carrying telomerase mRNA reduce brain inflammation after traumatic injury in mice

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Abstract

A single systemic dose of mTERT-LNPs increased cortical TERT mRNA and protein, and partially restored telomere length after traumatic brain injury.

Traumatic brain injury disrupts TERT biology, with reduced TERT mRNA and shortened telomeres observed at 3 days post-injury.
mTERT-LNPs were well tolerated in both laboratory and live animal tests.
Intravenous delivery of mTERT-LNPs localized to the injured brain and showed expected biodistribution.
Treatment with mTERT-LNPs significantly reduced microglial activation and suppressed pro-inflammatory cytokines.
Systemically, mTERT-LNPs lowered levels of serum C-reactive protein and malondialdehyde, indicating reduced inflammation and oxidative stress.
Several outcomes exhibited sex-dependent patterns.

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Traumatic brain injury (TBI) is a leading cause of chronic neurological disability, yet no disease-modifying therapy exists. Emerging evidence indicates that TBI activates cellular aging programs, including telomere erosion and persistent inflammation, that contribute to progressive neurodegeneration. Telomerase reverse transcriptase (TERT) preserves telomere homeostasis and provides cytoprotective effects in the central nervous system, but has not been therapeutically targeted after TBI. Here, we developed an mRNA nanotherapy consisting of mouse TERT mRNA encapsulated in lipid nanoparticles (mTERT-LNPs) and evaluated it in a controlled cortical impact model of moderate TBI. We first established that TBI transiently disrupts TERT biology, with reduced cortical TERT mRNA and shortened telomeres at 3 days post-injury (dpi), followed by partial recovery by 14 dpi. mTERT-LNPs were well tolerated in vitro and in vivo. Following intravenous delivery in the acute post-injury window, LNPs localized to the injured brain and displayed expected peripheral biodistribution. A single systemic dose increased cortical TERT mRNA and protein and partially restored telomere length at 3 dpi. TERT mRNA delivery significantly reduced Iba1+ microglial activation and suppressed pro-inflammatory cytokines, with modest increases in anti-inflammatory markers. Systemically, mTERT-LNPs lowered serum Creactive protein and malondialdehyde, indicating reduced peripheral inflammation and oxidative stress, without adverse effects on body weight or peripheral organ histology. Several outcomes showed sex-dependent patterns. Collectively, these data provide the first in vivo evidence that telomerase therapy can modulate telomere biology and neuroinflammation after TBI, supporting mRNA-LNP-mediated TERT restoration as a scalable, mechanistically grounded strategy for disease modification in TBI and related disorders.

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Telomerase mRNA-Lipid nanoparticles attenuate neuroinflammation after traumatic brain injury in mice.

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