Telomerase mRNA Nanoparticles Slash Brain Inflammation After Traumatic Injury

Traumatic brain injury (TBI) affects roughly 69 million people worldwide each year and remains without a single approved disease-modifying treatment. Beyond the immediate mechanical damage, TBI triggers secondary cascades—oxidative stress, neuroinflammation, mitochondrial dysfunction, and accelerated cellular aging—that drive progressive neurodegeneration and elevate long-term risk for Alzheimer's disease, Parkinson's disease, and chronic traumatic encephalopathy. Among these aging signals, telomere shortening has emerged as both a biomarker and an active pathological contributor after TBI, yet no therapy has targeted this mechanism.

To address this gap, the research team synthesized pseudouridine-modified mouse TERT (mTERT) mRNA and encapsulated it in ionizable lipid nanoparticles (LNPs) using a NanoAssemblr platform, achieving high encapsulation efficiency and favorable physicochemical properties. The formulation was first validated for safety in Neuro-2a neuronal cells across a 24–48 hour viability assay, showing no cytotoxicity at therapeutic concentrations. Six-month-old male and female C57BL/6J mice then underwent controlled cortical impact (CCI) surgery to produce moderate TBI, followed 30 minutes later by intravenous injection of mTERT-LNPs or controls.

The study first established the natural time course of TERT disruption after TBI: cortical TERT mRNA and protein were significantly reduced at 3 days post-injury (dpi), with telomeres measurably shortened, followed by partial spontaneous recovery by 14 dpi. mTERT-LNP treatment at 3 dpi reversed this pattern—boosting cortical TERT mRNA and protein and partially restoring telomere length (T/S ratio) compared to vehicle-treated TBI mice. Biodistribution imaging with Cy5.5-labeled LNPs confirmed localization to the injured brain alongside expected peripheral organ distribution (liver, spleen, lungs).

On the neuroinflammation front, mTERT-LNP delivery significantly reduced Iba1+ microglial activation in the injured cortex. Pro-inflammatory cytokine mRNAs—TNF-α, IL-1β, IL-6, and IL-18—were suppressed, while anti-inflammatory markers TGF-β and IL-10 showed modest increases. RNAscope FISH confirmed reductions in TNF-α and IL-1β transcript expression at the cellular level. Systemically, serum C-reactive protein (measured by western blot) and malondialdehyde (a lipid peroxidation marker) were both significantly lower in treated animals, pointing to reduced peripheral inflammation and oxidative stress without detectable organ toxicity.

Several outcomes displayed sex-dependent patterns, with males and females differing in magnitude of cytokine responses and telomere restoration, underscoring the importance of including both sexes in future studies. Key limitations include the short 3-day primary endpoint (insufficient to assess functional recovery or long-term neurodegeneration), the absence of behavioral outcome measures in this first report, and the use of a single CCI model that may not capture the full spectrum of human TBI pathology. Dose optimization and repeated-dosing regimens also remain to be explored before clinical translation.