Abstract
Peripheral nerve injury (PNI) affects over 20 million individuals globally each year, with incomplete nerve regeneration presenting a significant socioeconomic burden, particularly in diabetic patients. M2 macrophages play a crucial role in nerve regeneration by promoting tissue remodeling and repair. However, the post-injury microenvironment impedes the stabilization of the M2 phenotype, limiting their therapeutic potential. In vitro experiments demonstrate that macrophages modified with Netrin-1 can be polarized toward the M2 phenotype. Exosomes secreted by these Netrin-1-modified macrophages (N-Exos) significantly enhance endothelial cell proliferation, migration, tube formation, and survival under hyperglycemic conditions. The underlying mechanism is likely mediated by the activation of the PI3K/AKT/mTOR pathway through Unc5b. To further enhance the therapeutic effects of N-Exos, we incorporated these exosomes into a berberine-modified chitosan-based hydrogel (NE@CSB), thereby developing an innovative synergistic therapeutic approach. The NE@CSB hydrogel demonstrates favorable injectability, thermoresponsive sol-gel transition, strong tissue adhesion, and sustained release of exosomes. In the sciatic nerve injury model of diabetic mice, blood flow perfusion and histological analysis of injured nerves demonstrated that NE@CSB hydrogel could effectively enhanced angiogenesis and sciatic nerve regeneration. Overall, NE@CSB presents a promising and safe therapeutic strategy for the clinical treatment of diabetic PNI.
Similar content being viewed by others
Acknowledgements
Q.W., L.Z. and K.Y. contributed equally to this work. This work was financially supported by the National Natural Science Foundation of China (81971758, J.Q; 32201149, S.J; 82500591, Q.H), and the Major Scientific and Technological Innovation Project of Shandong Province (2025ZLGX04, 2024ZLGX07), Taishan Scholar Program of Shandong Province (NO.tsqn202507106).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare no conflict of interest.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Wang, Q., Zhu, L., Ye, K. et al. Chitosan thermosensitive hydrogel-based sustained-release system of Netrin-1 overexpressing macrophage exosomes: synergistic enhancement of angiogenesis and nerve regeneration. NPG Asia Mater (2026). https://doi.org/10.1038/s41427-026-00651-w
Received:
Revised:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41427-026-00651-w
