A proactive cholinergic-like acidic fibroblast growth factor delivery system for efficient protein enrichment and native drug release in the central nervous system to promote repair of injured spinal cord.

Abstract

Spinal cord injury (SCI) is a severe neurological trauma resulting in sensory deficits, impaired motor function, and compromised autonomic regulation. Acidic fibroblast growth factor (aFGF) with neuroprotective properties holds significant promise for promoting SCI repair. However, challenges of aFGF related to short blood circulation time, susceptibility to degradation, and severely restricted ability to cross blood-spinal cord barrier (BSCB) have hindered further exploration and utilization in SCI. In order to overcome these challenges, this study elaborately fabricated an innovative aFGF bionic intelligent delivery nanomedicine (abbreviated as aFGFND) via free radical polymerization technology to form a multifunctional thin polymer film on the surface of aFGF. The presence of this film enhanced aFGF's resistance against protease K degradation. In addition, hydrophilic polyethylene glycol (PEG) groups incorporated within the film contributed to extending the blood circulating time. Importantly, microvascular endothelial cells abundant with choline transporter (ChT) and nicotinic acetylcholine receptor (nAChR) could actively recognize and capture aFGFND based on choline analogues on the thin film to effectively facilitate drug to cross BSCB. Finally, under stimulation of reactive oxygen species (ROS) in damaged site, the phenylboronic ester bonds within the protective layer underwent degradation and subsequently released the loaded aFGF to exert neuroprotective effects. By efficiently enriching and native protein drug releasing, the repair efficiency of aFGF on SCI was significantly enhanced, including strengthening the inhibitory effect on the inflammatory microenvironment, reducing neuronal apoptosis, and promoting axonal and neural regeneration. Compared with free aFGF group, aFGFND significantly improved the recovery of mice motor function. The aFGFND could provide a new avenue for the treatment of CNS diseases.