Ultrasound-responsive nanotherapy promotes axonal regeneration after SCI via reactivating CREB/miR-129-5p signaling.

Spinal cord injury (SCI) remains a devastating neurological disorder with few effective therapeutic interventions due to the poor intrinsic regenerative capacity of adult central nervous system neurons. Here, we identified miR-129-5p as a downstream effector of cAMP-response element binding protein (CREB) signaling that promotes axonal growth by suppressing glycogen synthase kinase-3β (GSK3β). Leveraging this regenerative mechanism, we developed a low-intensity focused ultrasound (LIFU)-responsive biomimetic nanoplatform (CM-miR-CNP@PFP) for targeted SCI therapy. The platform comprises miR-129-5p/perfluoropentane (PFP)-loaded cationic lipid nanoparticles (CNPs) coated with hybrid membranes from RVG-engineered human umbilical cord mesenchymal stem cells and macrophages. The biomimetic coating grants superior immune evasion, prolonged circulation, and precise neuronal targeting. Under local LIFU irradiation, CM-miR-CNP@PFP undergoes acoustic droplet vaporization (ADV), a liquid-to-gas phase transition that enhances lesion-site accumulation and cellular delivery of miR-129-5p. In vivo, this ultrasound-responsive therapy significantly attenuated astroglial and fibrotic scar-associated changes, promoted axonal regeneration, and improved motor function. Overall, this biomimetic nanoplatform represents a promising strategy for targeted miRNA delivery and neural regeneration after SCI, with potential for further translational development.