After spinal cord injury (SCI), macrophages are rapidly activated and polarized to the M1 phenotype, and inhibition of M1-like macrophages has become a promising treatment for SCI. Metalloregulatory proteins can sense specific metal ions with high affinity and specificity and play a key role in immune regulation. Here, we screened various bioactive metal ions associated with metalloregulatory proteins and found that Zn2+ and Mn2+ could effectively inhibit M1 polarization. Based on these findings, we developed weakly alkaline ZnMn-based layered double hydroxides (ZnMn-LDHs) formed by self-assembly of Zn2+ and Mn2+ coordination to inhibit M1-like macrophages. ZnMn-LDHs effectively neutralize the acidic environment and promote the expression of metalloregulatory proteins, including metallothionein (MT), superoxide dismutase 1 (SOD1), and superoxide dismutase 2 (SOD2), resulting in a potent inhibitory effect on M1-like macrophages. More importantly, nerve growth factor (NGF) released by macrophages after ZnMn-LDHs regulation promoted the extension and spreading of Schwann cells. By integrating ZnMn-LDHs with silk fibroin (SF), ZnMn@SF injectable hydrogels for SCI repair were constructed. In vivo animal models further revealed the excellent anti-inflammatory effect of ZnMn@SF hydrogels in the treatment of SCI and promoted functional recovery. Our results highlight the importance of metal ion-regulated metalloregulatory proteins in inhibiting M1-like macrophages, providing a promising therapeutic strategy for SCI treatment.

Innovations:
1. The synergistic mechanism of Zn2+ and Mn2+ ions in regulating macrophage polarization was discovered and confirmed for the first time.
2. The ZnMn-LDHs material system with multiple functions was innovatively developed to achieve precise regulation of the immune microenvironment.
3. A new therapeutic strategy based on metalloregulatory proteins was established, providing new ideas for the treatment of spinal cord injury.

Inspiration from scientific research:
1. In the process of material design, biological mechanisms should be fully considered to achieve the synergy between material functions and biological effects.
2. Scientific research should focus on multidisciplinary cross-border, organically combining knowledge in fields such as materials science, immunology and neuroscience.

3. In the development of treatment strategies, attention should be paid to the integrity and systematicity of microenvironment regulation.

Extension of ideas:
1. Material design direction: explore the design strategy of new metal-based materials, study the synergistic effect of multiple ions, and develop intelligent response systems.
2. Mechanism research direction: in-depth study of the interaction between metal ions and cell signaling pathways, and explore the molecular mechanism of immune regulation.
3. Clinical transformation direction: conduct systematic preclinical research, evaluate biosafety, and optimize dosing regimens.
4. Application expansion direction: apply technology to other nervous system diseases and study treatment strategies for different types of injuries.
5. Intelligent development: develop intelligent controlled release systems, realize dynamic regulation of microenvironment, and establish real-time monitoring platforms.
6. Industrialization promotion: optimize large-scale production processes, establish quality control systems, and reduce production costs.
7. Tissue engineering application: Research and combine with stem cell therapy to explore new strategies for nerve regeneration and promote functional reconstruction.
8. Integrated diagnosis and treatment: Develop an intelligent system that integrates diagnosis and treatment to achieve precise treatment.