Nanoparticle-Mediated Brain-Targeted Drug Delivery for Methamphetamine Use Disorder: Advances, Challenges and Translational Perspectives.

Methamphetamine use disorder (MUD) poses a significant global health challenge, lacking FDA-approved pharmacotherapies. Despite extensive exploration of therapeutic targets and interventions, effective treatment remains scarce due to challenges in delivering therapeutic agents to relevant brain regions at effective concentrations. Nanoparticle-mediated delivery offers a promising approach for transporting various therapeutic cargos to the central nervous system, including small molecules, nucleic acids, peptides, proteins, and gene-editing systems. However, the application of nanomedicine strategies in addressing the unique pathophysiological characteristics of MUD has not been systematically assessed. This review presents a problem-focused analysis of how lipid-based, polymeric, inorganic, biological, and hybrid nanocarriers tackle successive delivery obstacles such as systemic stability, blood-brain barrier (BBB) penetration, brain region-specific distribution, and controlled release of intracellular cargo. We compare preclinical nanotherapeutic approaches encompassing small-molecule neuroprotective agents, anti-METH vaccines, gene-silencing RNAs, neurotrophic proteins, and emerging gene-editing methods, outlining their respective benefits, limitations, and design considerations. Additionally, we explore key factors influencing nanomedicine performance in MUD, including protein corona formation, the impact of METH-related BBB dysfunction and neuroinflammation on nanoparticle distribution, and the disparity between acute animal models and chronic human MUD with relapse tendencies. In conclusion, we present a systematic framework for aligning nanocarrier characteristics with distinct delivery obstacles and therapeutic needs. We also emphasize forthcoming avenues such as disease-triggered nanocarriers, targeted delivery to specific regions, combined nanomedical approaches, theranostic strategies, and standardized assessments of biodistribution, effectiveness, safety, and translational potential.