Masking macrophage injury sensing via poly I sustained release system reduces inflammation and fibrosis.

Abstract

Tissue fibrosis following injury often leads to severe complications in humans. Recent research highlights that macrophage hypermigration and activation play a critical role in fibrosis development. Emerging evidence suggests that macrophage sensing of tissue injury via damage-associated molecular patterns (DAMPs) is crucial for their migration and activation. Excessive injury sensing is linked to macrophage hyperactivity, aberrant inflammation, and fibrosis. Recent studies have shown that polyinosinic acid (Poly I) can reduce macrophage activation by inhibiting signaling pathway associated with macrophage scavenger receptors (MSR). Based on this, we developed an electrospun polycaprolactone (PCL) fibrous membrane incorporating Poly I (PCL-Poly I) to ensure its early sustained release and function as an effective physical barrier. In vitro and in vivo results showed that Poly I could mask macrophage early injury sensing by downregulating MSR1/PI3K/AKT/SPP1 pathway. The local implantation of PCL-Poly I could reduce the early aggregation and activation of macrophages in the epidural fibrosis (EF) zone, thus suppressing the fibroblast activation and EF progress, with its therapeutic efficacy lasting up to 8 weeks after laminectomy. In conclusion, this study demonstrates the potential of biomaterial-based strategies to modulate immune responses, offering a novel upstream solution for treating fibrosis-related conditions.