Recent Innovations in Drug Delivery Systems for Amyotrophic Lateral Sclerosis: Past, Present and Future.

Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive and fatal neurodegenerative disorder characterized by degeneration of upper and lower motor neurons, resulting in severe muscle weakness, respiratory failure, and death. Despite several pharmacological therapies having been approved, their clinical benefit remains limited due to poor central nervous system penetration, rapid metabolic clearance, and low patient compliance. Overcoming these pharmacokinetic and pharmacodynamic limitations remains a major challenge in ALS management. Recent advances in drug delivery have focused on brain-targeted strategies, improved bioavailability, and sustained or controlled-release systems. Nanocarriers, including lipid and polymeric nanoparticles, dendrimers, and mesoporous silica systems, facilitate blood-brain barrier traversal, protect labile drugs, and enable surface functionalization for receptor-mediated targeting. Biologically derived carriers such as exosomes and extracellular vesicles further enhance targeted delivery while minimizing immunogenicity. In parallel, noninvasive approaches such as mucoadhesive polymers, intranasal, and nose-to-brain delivery systems, including microneedle-based platforms, offer promising alternatives to bypass first-pass metabolism and improve patient adherence. Additionally, emerging therapeutic modalities, including gene therapy, stem cell-based interventions, and neuromodulation, are increasingly integrated with advanced delivery technologies. This article critically analyzes current ALS therapies, highlights recent breakthroughs in advanced drug delivery systems, and discusses future perspectives for achieving meaningful clinical outcomes.