Macrophage Plasma Membrane Coating Enhances Nerve Delivery of Stably Labeled Polymeric Nanoparticles

Abstract Acute inflammatory demyelinating polyneuropathy (AIDP) is the leading cause of acute autoimmune flaccid paralysis and the most common subtype of Guillain–Barré syndrome (GBS). A key pathogenic event in AIDP is localized inflammation of the blood–nerve barrier (BNB), which enables transendothelial migration of circulating autoreactive leukocytes into peripheral nerves. Experimental autoimmune neuritis (EAN), a well-established rat model of GBS, has provided critical insights into AIDP pathophysiology; however, therapeutic options remain limited, in part due to the restrictive BNB. Nanomedicine offers a unique approach to deliver a therapeutic payload across the BNB and to nerves while minimizing off-target effects and systemic toxicity. We previously found that EAN-associated BNB permeability promotes passive accumulation of long-circulating nanoparticles (NPs) in inflamed nerves at advanced disease stages. While promising, we hypothesize that surface modification with ligands that target the underlying pathology can enhance site-specific targeting and improve NP delivery to EAN nerves. Here, we developed a NP-based drug delivery system using rat macrophage-derived plasma membrane vesicles (mNPs) to target affected peripheral nerves in EAN, leveraging the inflammation-driven pathology of the disease. We demonstrate that mNPs exhibit enhanced specificity and accumulation within inflamed nerves at both early and advanced stages of EAN. Interaction with the BNB is intercellular adhesion molecule-1 (ICAM-1)-dependent and leads to association with endoneurial cellular targets, including myelin-associated glia. These findings highlight the potential of macrophage-mimetic NPs as a platform for targeted therapeutic delivery and support their use as a vector for repurposing promising therapeutics for immune-mediated neuropathies.