Noninvasive nanoparticle-directed therapy to the peripheral nervous system

PROJECT ABSTRACT The blood-nerve barrier (BNB) is a highly selective boundary that often prevents the non-invasive delivery of drugs to nerves, which is why nerve injuries and diseases remain difficult to treat1. The BNB highly limits the non-invasive treatment of peripheral neuropathies, meaning that there are few treatments available depending on the cause, despite severe cases that can result in debilitating nerve alterations. Even with traumatic peripheral nerve injuries where regeneration spontaneously occurs, functional recovery is often very poor since regeneration is abysmally slow. Current gold standard for addressing these traumatic nerve injuries involves surgical interventions. However, even with these surgical interventions, most patients do not obtain functional recovery if regeneration distances exceed a few centimeters. Here, we propose the design and implementation of a local and systemically administered nerve-targeting polymersome platform that can penetrate peripheral nerves and lead to functional recovery after peripheral nerve crush injury. We will investigate the effect of adding two targeting ligands, Apolipoprotein E (ApoE) and Rabies Virus Glycoprotein peptide RVG-9R, to the polymersome surface on BNB penetration. Preliminary data suggest that RVG-9R enables delivery through the potentially injured blood-nerve barrier and ApoE is assists in the retaining polymersomes in the nerve. We will elucidate the mechanisms associated with these ligand-based approaches by studying alterations in receptor expression on the BNB and neural cells. We will study the pharmacokinetics of ligated particles after sciatic nerve injury, correlating changing behavior with receptor expression. We will then investigate the nerve regenerative effects of two different biologic drugs developed by co-I Jeff Twiss, a G3BP1 peptide and siRNA targeting prenyl-Cdc42 mRNA, delivered through polymersomes. This proposed work represents a novel, potentially paradigm shifting approach to selectively deliver therapeutics to the peripheral nervous system through non-invasive systemic injections, with the goal of enabling functional recovery post nerve injury. However, the modular nature of the polymersome system and the ability to substitute various therapeutic payloads enables the extensions of findings to acquired and inherited nerve diseases.