Modulation of the Crosstalk between Schwann Cells and Macrophages for Nerve Regeneration: A Therapeutic Strategy Based on a Multifunctional Tetrahedral Framework Nucleic Acids System

Peripheral nerve injury (PNI) is currently recognized as one of the most significant public health issues and affects the general well-being of millions of individuals worldwide. Despite advances in nerve tissue engineering, nerve repair still cannot guarantee complete functional recovery. In the present study, an innovative approach is adopted to establish a multifunctional tetrahedral framework nucleic acids (tFNAs) system, denoted as MiDs, which can integrate the powerful programmability, permeability, and structural stability of tFNAs, with the nerve regeneration potential of microRNA-22 to enhance the communication between Schwann cells (SCs) and macrophages for more effective functional rehabilitation of peripheral nerves. Relevant results demonstrate that MiDs can amplify the ability of SCs to recruit macrophages and facilitate their polarization into the pro-healing M2 phenotype to reconstruct the post-injury microenvironment. Furthermore, MiDs can initiate the adaptive intracellular reprogramming of SCs within a short period to further promote axon regeneration and remyelination. MiDs represent a new possibility for enhancing nerve repair and may have critical clinical applications in the future.