Amplification of Metalloregulatory Proteins in Macrophages by Bioactive ZnMn@SF Hydrogels for Spinal Cord Injury Repair
Xiaoliang Cui, Cheng Huang, Yechen Huang, Yuxuan Zhang, Jie Wu, G.S. Wang, Xiaozhong Zhou, Jun Zhang, Li Wang, Liang Cheng, Ke‐Qin Zhang
Abstract
Macrophages are rapidly activated and polarized toward the M1 phenotype after spinal cord injury (SCI), and inhibiting M1-like macrophages has emerged as a promising SCI treatment approach. Metalloregulatory proteins, which sense specific metal ions with high affinity and specificity, play a critical role in immune regulation. Here, we screened various bioactive metal ions associated with metalloregulatory proteins and discovered that Zn 2+ and Mn 2+ effectively suppressed M1 polarization. Based on these findings, mildly alkaline ZnMn-based layered double hydroxides (ZnMn-LDHs) self-assembled from Zn 2+ coordinated with Mn 2+ were developed to inhibit M1-like macrophages. ZnMn-LDHs effectively neutralized the acidic environment and promoted the expression of metalloregulatory proteins, including metallothionein (MT), superoxide dismutase 1 (SOD1), and superoxide dismutase 2 (SOD2), thereby eliciting robust M1-like macrophage inhibition. More importantly, nerve growth factor (NGF) released by macrophages following the regulation by ZnMn-LDHs promoted the elongation and spreading of Schwann cells. By integrating ZnMn-LDHs with silk fibroin (SF), ZnMn@SF injectable hydrogels were constructed for SCI repair. An in vivo animal model further revealed the excellent anti-inflammatory effects of the ZnMn@SF hydrogels in treating SCI, which promoted functional recovery. Our findings underscore the importance of metalloregulatory proteins regulated by metal ions in inhibiting M1-like macrophages, providing a promising therapeutic strategy for SCI treatment.