Work

AI‐Designed TREM1‐Targeted LYTAC Nanoparticles Reprogram the Neuroimmune Microenvironment in Traumatic Brain Injury

Year: 2026

Type: article

Abstract: Secondary neuroinflammation drives progressive damage after traumatic brain injury (TBI), but therapeutics that modulate key inflammatory amplifiers remain limited. Here, we identify infiltrating macrophages as the predominant TREM1-expressing population in TBI human and mouse brain and show that TREM1 deletion attenuates neuroinflammation, preserves neurovascular integrity, and improves neurological and behavioral recovery after TBI. To develop a pharmacological strategy, we designed a de novo TREM1-binding peptide, converted it into a mannose-6-phosphate lysosome-targeting chimera (LYTAC), and delivered it using an Angiopep-2-functionalized, pH-responsive dendrimer nanoparticle. This Angiopep-2/PAMAM/TPA/LYTAC nanoparticle (APTL-NP) enhanced brain delivery, promoted lesion-responsive payload release, reduced TREM1 protein abundance in vivo, and outperformed free degrader and LP17 in suppressing inflammatory mediators, edema, blood-brain barrier disruption, neuronal apoptosis, and behavioral deficits. Single-cell transcriptomics suggested remodeling of myeloid, astrocytic, vascular, and SPP1/CXCL-associated communication programs. These findings support targeted TREM1 reduction as a strategy for modulating secondary TBI injury.

Source: Advanced Science

DOI: 10.1002/advs.77972