Noninvasive method for achieving the regeneration of damaged nerves via ultrasonic nasal drops

Repair and regeneration of damaged neurons is a promising therapeutic strategy for central nervous system (CNS) diseases such as ischemic stroke (IS). However, achieving efficient neuronal repair and regeneration after CNS injury through noninvasive methods remains a significant challenge. Therefore, this study proposes, for the first time, an ultrasonic nasal drop formulation that induces efficient regeneration of damaged neurons through electropharmacological coupling in an noninvasive manner. Liposomes containing the natural anti-inflammatory drug Timosaponin B-II (TB) were coated onto barium titanate nanoparticles (BTO) to form LTO@TB. Using microfluidic technology and a Schiff base reaction, LTO@TB was encapsulated into aldehyde-based and methacrylate-modified microspheres (MS) to create the ultrasonic nasal drop MS@LTO@TB. The aldehyde groups of MS@LTO@TB spontaneously formed amide bonds with the numerous amino groups in the nasal mucosa, facilitating specific adhesion. Due to its enhanced bioadhesion and efficient transmembrane transport, LTO@TB was continuously and noninvasively delivered to the brain when administered nasally. Additionally, under ultrasonic stimulation, LTO@TB in the brain exerted an electropharmacological coupling effect, achieving noninvasive electrical stimulation of damaged neurons. MS@LTO@TB modulated microglial phenotypes, restored electrical signal conduction among damaged neurons, reshaped the inflammatory microenvironment, reduced neuronal apoptosis, activated the PI3K/AKT signaling pathway, and promoted axonal regeneration. MS@LTO@TB also showed the unique ability to alleviate inflammation and promote neuronal remodeling in a mouse model of middle cerebral artery occlusion/reperfusion (MCAO/R). This study presents a promising strategy involving the nasal administration of ultrasonic nasal drops as a noninvasive and efficient treatment for CNS injuries.