Translational roadmap of BBB-targeted nanoparticle strategies for neuroregenerative therapy in neurodegenerative diseases

Abstract

Neuroregeneration has drawn scientific attention due to its therapeutic potential for neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and traumatic brain injury (TBI). A major obstacle in delivering neuroregenerative and neuroprotective drugs is crossing the blood–brain barrier (BBB)—a selective, physiological barrier that protects the central nervous system (CNS) from circulating toxins and pathogens. While this protective role is essential for maintaining CNS homeostasis, it also limits therapeutic efficacy and increases the risk of systemic side effects due to off-target accumulation. To overcome these challenges, recent advances in nanoparticle engineering have focused on enhancing BBB transcytosis by employing biologically inspired surface modifications. In this review, we highlight three mechanistically distinct approaches: (1) transporter-mediated transcytosis (TMT), which uses glucose or amino acid conjugation; (2) receptor-mediated transcytosis (RMT) via ligands such as transferrin or angiopep-2; and (3) adsorptive-mediated transcytosis (AMT), utilizing cationic polymer coatings or cell-penetrating peptides (CPPs).