Minimally invasive delivery of peptides to the spinal cord for behavior modulation

Abstract

The blood-spinal cord barrier (BSCB) tightly regulates molecular transport from the blood to the spinal cord. Herein, we present a novel approach for transient modulation of BSCB permeability and localized delivery of peptides into the spinal cord for behavior modulation with high spatial resolution. This approach utilizes optical stimulation of vasculature-targeted nanoparticles and allows delivery of BSCB-nonpermeable molecules into the spinal cord without significant glial activation or impact on animal locomotor behavior. We demonstrate minimally invasive light delivery into the spinal cord using an optical fiber and BSCB permeability modulation in the lumbar region. Our method of BSCB modulation allows delivery of bombesin, a centrally-acting and itch-inducing peptide, into the spinal cord and induces a rapid and transient increase in itching behaviors in mice. This minimally invasive approach enables behavior modulation without genetic modifications and is promising for delivering a wide range of biologics into the spinal cord for behavior modulation and potentially therapy.Significance StatementSpinal cord diseases and disorders are common and cause significant disability, including chronic pain, paralysis, cognitive impairment, and mortality. The blood-spinal cord barrier is a considerable challenge for delivery by systemic therapeutic administration. We developed an optical approach for effectively and safely delivering molecules to the spinal cord to overcome this barrier. The fiberoptic method is minimally invasive and overcomes challenges that previous technologies face, including the complicated bone structure and standing waves that complicate BSCB opening using ultrasound. Optical stimulation offers unprecedented spatial resolution for the precise delivery in intricate spinal cord structures. Significantly, our approach modulates animal behavior (i.e., itch) without genetic modifications and demonstrates the potential for delivery of biologics such as peptides into the spinal cord.

Strategies for enhanced gene delivery to the central nervous system

“…A latest study introduced an optical technology to address the challenge of overcoming the BSCB for targeted molecular delivery to the spinal cord. 115 A novel approach involves the transient modulation of BSCB permeability for localized molecular (peptide and gene vectors) delivery with exceptional spatial precision ( Fig. 6A–C ).…”

Recent advances in stimuli-responsive controlled release systems for neuromodulation

“…15,28 Recently, Qin et al introduced an innovative technique for optically modulating the BBB through laser stimulation of gold nanoparticles targeted at tight junctions, enhancing the permeability of both the BBB and the blood-spinal cord barrier. 21,29 Employing this technique enabled the administration of bombesin to the spinal cord, effectively inducing itch responses in mice.…”