# Clec7a-targeted Res@GelMA hydrogels regulate macrophage polarization to reduce neuroinflammation and promote spinal cord repair

## TL;DR

A new hydrogel material reduces spinal cord inflammation and promotes healing by regulating immune cells.

## Contribution

A Res@GelMA hydrogel was developed to target macrophage polarization and reduce neuroinflammation after spinal cord injury.

## Key findings

- Res@GelMA promotes M2 macrophage polarization and reduces inflammatory factors like IL-1β, IL-6, and TNF-α.
- Clec7a was identified as a key target gene regulated by Res@GelMA, which inhibits the TLR2/TLR4-p38 MAPK signaling pathway.
- In a mouse model, Res@GelMA improved tissue repair and motor recovery after spinal cord injury.

## Abstract

Excessive inflammation driven by macrophage phenotype imbalance is a key pathological barrier hindering neural repair after spinal cord injury (SCI). Here, methacryloyl gelatin hydrogel (GelMA) loaded with natural anti-inflammatory agent resveratrol (Res) was designed and synthesized. Scanning electron microscopy (SEM), x-ray diffraction (XRD), fourier-transform infrared spectroscopy (FT-IR), Ultraviolet (UV) and rheological characterization confirmed that Res-loaded GelMA hydrogel (Res@GelMA) was successfully synthesized. High-Performance Liquid Chromatography (HPLC) analysis demonstrated sustained Res release. CCK8 and cell adhesion experiments confirmed that Res@GelMA treatment did not affect the cell function of RAW264.7 and had good cell compatibility. Flow cytometry, Enzyme-Linked Immunosorbent Assay (ELISA) and western blot assays revealed that Res@GelMA treatment promoted RAW264.7 to M2 polarization, while reducing the levels of inflammatory factors (IL-1β, IL-6, TNF-α) and down-regulating the expression of IL-1R1/MyD88/TNFR1 inflammatory signaling proteins. Transcriptome sequencing combined with functional screening identified C-type lectin receptor Clec7a as a key target gene regulated by Res@GelMA. Importantly, knockdown of Clec7a and Res@GelMA were both anti-inflammatory, promoted M2 polarization, and blocked the activation of the TLR2/TLR4-p38 MAPK signaling axis. In the SCI mouse model, local implantation of Res@GelMA significantly improved tissue pathological damage and enhanced motor function recovery compared with free Res or blank GelMA. In addition, Res@GelMA achieved systemic anti-inflammation by downregulating the Clec7a-TLR-p38 pathway in the injured area and promoting M2 polarization. This study developed an anti-inflammatory hydrogel material that can regulate the phenotype of macrophages, laying a theoretical and technical foundation for the development of neural repair strategies targeting the inflammatory microenvironment.

The online version contains supplementary material available at 10.1186/s13018-025-06631-0.