A long-acting injectable nanoparticle-hydrogel depot enables sustained IGF-1 delivery to reverse chronic denervation.

Chronic denervation following peripheral nerve injury leads to progressive muscle atrophy and Schwann cell dysfunction that severely limit functional recovery, yet no therapies effectively sustain trophic support over the prolonged regenerative period. Here, we develop a long-acting injectable (LAI) biomaterial platform that enables sustained local delivery of insulin-like growth factor-1 (IGF-1). The system encapsulates IGF-1 in poly(ethylene glycol)-b-polycaprolactone nanoparticles and embeds nanoparticles within an injectable nanofiber-hydrogel composite, enabling six-week local IGF-1 delivery with preserved bioactivity and tissue retention. In a rat chronic denervation model with delayed nerve repair, the IGF-1 LAI increased grip strength by 29.1%, myelinated axon counts by 186.2%, and myofiber cross-sectional area by 88.4%. In a non-human primate model, repeated six-week dosing maintained intramuscular IGF-1 levels and improved functional recovery by 57.0%, accompanied by reduced fibrosis and increased reinnervation. These findings establish a translational biomaterial strategy for sustained protein delivery and disease-modifying treatment of chronic denervation.