Adoptive Treg therapy using chitosan conduits/self-assembled peptide hydrogels for enhanced immunomodulation and peripheral nerve regeneration

Tissue healing is regulated by the immune system, and harnessing the endogenous regenerative capacity has recently become an active area of research. Regulatory T cells (Tregs) are a subset of adaptive immune cells known for their potent immunosuppressive abilities and crucial role in maintaining tissue homeostasis. The use of Tregs shows great potential as a clinical approach for promoting tissue repair and regeneration. However, systemic immune suppression induced by Tregs presents significant risks to patients, including increased susceptibility to infections, nephrotoxicity, and the development of lymphoproliferative disorders. In the case of peripheral nerves, especially those with long-gap defects, the efficiency of spontaneous regeneration diminishes or may even cease entirely due to the complex and precisely regulated microenvironments within the body. While the local application of Tregs has shown effective immune regulatory effects, much remains unknown about their impact and underlying mechanisms in nerve regeneration. We synthesized a nano artificial growth factor hydrogel scaffold incorporating a cyclic BDNF mimetic sequence, designed to specifically bind to its receptor and activate Schwann cells and nerve cells. The hydrogel scaffold encapsulating Tregs preserves their proliferative potential and key Foxp3 phenotype, mitigating functional impairments caused by their inherent instability and susceptibility to polarization. Importantly, we report that chitosan conduits filled with Tregs, supported by a BDNF self-assembled peptide hydrogel, promote peripheral nerve regeneration in a 6-mm sciatic nerve defect model in mice. In addition to effectively regulating angiogenesis and macrophage polarization, they directly accelerate nerve regeneration, myelination, and functional recovery. We have developed a biologic approach for neural applications that ensures preservation, stability, and the creation of biomimetic neural microenvironments. This paves the way for new, viable strategies to leverage biomaterial-mediated Tregs regeneration mechanisms in treating peripheral nerve injuries and advancing clinical translation. © 2025 Elsevier B.V.