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

Abstract

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.