An injectable wet-adhesive hydrogel for wireless ultrasound-driven physico-chemical synergistic repair of cavernous nerve injury via piezoelectricity and nitric oxide release

Neurogenic erectile dysfunction (NED) seriously affects the physical and mental health of patients, and currently there is a lack of satisfactory treatment plans. Traditional methods for peripheral nerve injury, such as nerve catheterization, are not suitable for cavernous nerves, which are small in diameter and closely attached to the prostate tissue. A tissue-friendly strategy for therapeutic factor delivery in such situations is also needed. Nitric oxide (NO) and electrical stimulation are two key factors in the repair of penile cavernous nerves; their mechanisms of action are complementary, but there is currently no strategy that can simultaneously address both to activate the repair potential of cavernous nerves following injury. Based on this, a multifunctional hydrogel system (PEG@BaTiO₃-PDA-BNN6@PEDOT:DSS) is developed in the study. The system is composed of a wet-adhesive hydrogel and incorporates NO-releasing nanogenerators. The injectability and tissue adhesion of this hydrogel allow it to be adapted to any injury site. NO-releasing nanogenerators are mechanosensitive, so that NO/microcurrent production can be precisely regulated by ultrasound to promote the repair of injured nerves. In a neural cell model, microcurrent is demonstrated to promote axon growth by activating the VGCC/Ca²⁺/CaMKII/CREB signaling pathway, while NO promotes nerve repair by activating the NO/sGC/cGMP signaling pathway. In NED rats, the hydrogel adhered to the surface of cavernous nerves by injection only. Under the synergistic effect of NO and electrical stimulation, the hydrogel system significantly promoted nerve repair and improved erectile function. Collectively, this study provides an innovative, neural-structure-friendly strategy for peripheral nerve injury repair.