Spinal Cord Injury (SCI) is a devastating neurological disorder that often leads to permanent neural dysfunction. Current treatments fail to address the core challenges of insufficient intrinsic axonal regeneration, lack of directional guidance, and an inhibitory pathological microenvironment. There is an urgent need for synergistic therapeutic strategies that integrate structural support, molecular regulation, and microenvironment optimization to achieve effective neural function recovery.

Now, a joint research team from Zhejiang University and Fuzhou University has developed a collaborative treatment platform combining a multichannel 3D-printed bioactive scaffold with a small interfering RNA (siRNA) delivery system. This innovative approach simultaneously provides physical guidance, improves the inhibitory microenvironment, and activates the intrinsic regenerative capacity of neurons. In animal experiments, the combined therapy significantly enhanced long-distance parallel axon regeneration, promoted myelination and synaptic formation, and remarkably improved hindlimb motor function in SCI rats, with BBB scores significantly higher than other treatment groups from the 6th week post-surgery.

"The treatment of spinal cord injury has long been limited by the inability of single strategies to tackle multiple pathological barriers," said corresponding author Dr. Wei Wei, a professor at Zhejiang University. "Our integrated platform merges physical cues, biological signaling, and microenvironment regulation, offering a promising solution to overcome the bottlenecks in SCI therapy and advancing the translation from basic research to clinical application."

Jin Zhang, a professor at Fuzhou University and co-corresponding author, added: "The precision 3D-printed scaffold, functional hydrogel, and siRNA delivery system work synergistically to reconstruct neural circuits. This design not only enhances axonal regeneration but also ensures functional integration, laying a solid foundation for future clinical transformation."

Synergistic Triple-Function Design
The research team integrated three core functions into a single therapeutic system through innovative design:
1. A high-precision 3D-printed GM-PEGDA scaffold with parallel channels provides clear "growth paths" for axon regeneration, matching the structural characteristics of spinal cord conduction bundles.
2. GM-RA4IV bioactive hydrogel filled in the channels mimics the natural extracellular matrix, delivers neurotrophic support, and regulates the immune microenvironment by inhibiting the activation of harmful M1 macrophages.
3. siRNA-loaded lipid nanoparticles (siRNA@LNPs) efficiently knock down the PTEN gene, activate the mTOR signaling pathway, and significantly enhance the intrinsic regenerative potential of neurons.

The GM-RA4IV hydrogel exhibits excellent physical properties, including rapid gelation within 10 seconds under UV irradiation, a porous structure with an average pore size of 16.44 ± 4.03 μm, and stable mechanical strength (284.67 ± 12.83 Pa). It maintains structural integrity in vivo for approximately one month, providing long-term support for axon regeneration. Immunofluorescence analysis confirmed that the combined therapy induced axons to regenerate in a long-distance, parallel manner with an average projection angle of only 9.67° ± 6.82°, and the number of regenerated axons doubled compared to control groups.

Research Significance and Future Outlook
This study marks a critical advancement in SCI treatment by pioneering the integration of multichannel 3D-printed bioactive scaffolds, laminin-derived peptide hydrogels, and PTEN-targeted siRNA delivery—breaking the limitations of traditional single-target strategies. By simultaneously resolving the three core bottlenecks (insufficient intrinsic axonal regeneration, lack of directional guidance, and inhibitory microenvironment), it realizes the synergistic effect of physical support, molecular regulation, and microenvironment optimization. Moreover, the research identifies the key role of the Ephrin/Eph signaling pathway in guiding parallel axon regeneration, deepening the understanding of molecular mechanisms underlying SCI repair and opening new avenues for targeted therapy research. The GM-RA4IV hydrogel’s favorable properties (appropriate mechanical strength, low swelling rate, controllable degradability), the 3D-printed scaffold’s structural compatibility with spinal cord tracts, and the siRNA delivery system’s high efficiency and low toxicity collectively lay a robust material and technical foundation for clinical translation, bridging the gap between basic SCI research and clinical application.

For future development, the team plans to expand the therapeutic platform’s clinical translation scenarios: validating its efficacy in more clinically relevant models, such as chronic SCI cases, complete spinal cord transection models (simulating severe injuries), and large animal models. Additionally, efforts will focus on optimizing intervention timing and surgical delivery methods, addressing practical challenges like large-scale production and long-term implantation stability to advance the strategy from rat experiments to human clinical trials. The team also intends to explore combinations of this integrated platform with other therapies—such as stem cell treatment, electrical stimulation, and organoids—to strengthen "axon highway-pathway network" construction and further improve neural circuit regeneration outcomes.

The complete study is accessible via DOI:10.34133/research.0951