Nano-Immunomodulators for Directing Macrophage Fate to Enhance Peripheral Nerve Repair: Advances, Challenges, and Translational Perspectives

Shaoyan Shi,1 Xingxing Yu,2 Xuehai Ou,1 Qian Wang,1 Dong Hu3 1Department of Hand Surgery, Honghui Hospital, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 2Department of Laboratory Medicine, Xi’an Medical College, Xi’an, Shaanxi, People’s Republic of China; 3Department of Foot and Ankle Surgery, Honghui Hospital, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of ChinaCorrespondence: Dong Hu, Department of Foot and Ankle Surgery, Honghui Hospital, Xi’an Jiaotong University, Xi’an, Shaanxi, 710000, People’s Republic of China, Email [email protected]: Peripheral nerve injury remains a major clinical challenge due to inefficient axonal regeneration and limited therapeutic options. As central regulators of the repair process, macrophages dynamically transition from a pro-inflammatory to a pro-regenerative phenotype, coordinating debris clearance, axonal regrowth, remyelination, and functional restoration. However, disruptions in macrophage polarization—particularly in aging or chronic injury contexts—compromise regenerative outcomes. Here, we present a comprehensive overview of nano-immunomodulatory strategies designed to precisely direct macrophage fate for targeted peripheral nerve repair. Engineered organic, inorganic, and topography-guided nanoparticles provide spatiotemporal control of macrophage behavior via surface modifications and responsive designs, enabling phenotype reprogramming, microenvironment remodeling, and synergistic interactions with Schwann cells and regenerating axons. To present a balanced perspective, we also highlight key translational barriers—including long-term biocompatibility, immune safety, large-scale manufacturing, and regulatory challenges—that currently limit clinical application. This review highlights nano-immunomodulation as a promising approach for modulating immune-neural interfaces, offering a path toward precision therapies for peripheral nerve injury.Keywords: peripheral nerve injury, nanonedicine, macrophage, precision therapy, immune