A Strategy Involving Microporous Microneedles Integrated with CAR-TREM2-Macrophages for Scar Management by Regulating Fibrotic Microenvironment

Abstract

Dipeptidyl peptidase 4 (DPP4) positive fibroblasts play a pivotal role in scar development following skin injury. Heterogeneous vascular endothelial cells (ECs) within scarred areas retain the capacity to drive tissue regeneration and repair. Simultaneously, TREM2 macrophages play a crucial role in the progression and resolution of fibrosis by engaging in mutual regulation with ECs. However, effective strategies to inhibit scar formation through multi-factor regulation of the scar microenvironment remain a challenge. Here, CAR-TREM2-macrophages (CAR-TREM2-Ms) capable of targeting DPP4⁺ fibroblasts and modulating ECs subtype within the scar microenvironment are engineered to effectively prevent scarring. Hydrogel microporous microneedles (mMNs) are employed to deliver CAR-TREM2-Ms, which can effectively alleviate scar. Single-cell transcriptome sequencing (scRNA-seq) analysis reveals that CAR-TREM2-Ms can modify ECs fibrotic phenotype and regulate fibrosis by suppressing the profibrotic gene leucine-rich-alpha-2-glycoprotein 1 (Lrg1). In vitro experiments further demonstrate that CAR-TREM2-Ms improve the scar microenvironment by phagocytosing DPP4⁺ fibroblasts and suppressing TGFβ secretion. This, in turn, inhibits the phenotypic conversion of LRG1 ECs and provides multifactorial way of alleviating scars. This study uncovers the evidence that mMNs attached to CAR-TREM2-Ms may exert vital influences on skin scarring through the regulation of the skin scar microenvironment, providing a promising approach for treating posttraumatic scarring.

Keywords: CAT‐TREM2‐macrophages; microporous microneedles; single cell transcriptome sequencing; skin scar.