Dorsal Root Ganglion-Targeted DNA Origami Delivery of IL1RN for Skeletal Growth and Repair

Background/Objectives: Sensory nerves, as essential peripheral nerves, innervate bone and release various neuroactive substances—including neurotransmitters, neuropeptides, and neurocrine factors—that participate in bone growth, remodeling, and metabolism. Interleukin-1 receptor antagonist (IL1RN), an endogenous anti-inflammatory mediator, is a key regulatory molecule in the pathogenesis of inflammatory diseases such as osteoarthritis and rheumatoid arthritis. However, its role as a sensory neurocrine factor in the regulation of bone tissue has rarely been investigated. This study aimed to explore the regulatory effects of sensory nerve–derived IL1RN on bone tissue. Methods: A dorsal root ganglion (DRG)-targeted delivery system was developed using DNA origami technology to load IL1RN protein or IL1RN-targeting siRNA and was functionalized with a DRG-homing peptide. Bone defect and age-related bone loss models were established in C57BL/6 mice to preliminarily investigate the regulatory role of IL1RN secreted from sensory nerve endings in bone tissue. Results: IL1RN suppressed bone resorption and promoted new bone formation at defect sites. In the age-related bone loss model, IL1RN preserved the integrity of the growth plate. These findings indicate that sensory nerve–derived IL1RN may participate in the regulation of bone repair and skeletal homeostasis. Conclusions: IL1RN may serve as a potential therapeutic target for DRG-mediated regulation of bone repair. These findings suggest that DRG-targeted modulation of IL1RN may represent a potential approach for investigating and regulating sensory nerve–associated bone repair.