Smart alginate-based biomaterials for neurodegenerative disease therapy: Innovations in delivery, regeneration, and...

Neurodegenerative diseases and central nervous system (CNS) injuries remain among the most challenging disorders to treat due to their complex pathophysiology, limited regenerative capacity, and the presence of the blood-brain barrier (BBB), which severely restricts therapeutic delivery. Despite extensive research efforts, most current interventions are palliative and fail to modify disease progression. Biomaterial-based strategies have emerged as promising adjuncts to conventional therapies, with alginate-based systems attracting increasing attention due to their biocompatibility, mild aqueous processing, and tunable physicochemical properties. This review critically examines the role of alginate-based biomaterials in CNS drug delivery, tissue engineering, and regenerative medicine, with particular emphasis on their ability to address key translational barriers, including BBB penetration, immune compatibility, and localized, sustained therapeutic release. We discuss how alginate can be engineered into nanoparticles, hydrogels, microspheres, and three-dimensional scaffolds to engage distinct transport mechanisms such as receptor-mediated transcytosis, adsorptive-mediated uptake, and nose-to-brain delivery while preserving the stability of labile bioactive cargos. Quantitative design parameters relevant to CNS applications, including stiffness ranges, degradation kinetics, and porosity, are highlighted to support rational material selection. Importantly, this review distinguishes between the structural and delivery functions of alginate as a carrier material and the biological effects mediated by encapsulated therapeutic agents, avoiding overstatement of alginate's intrinsic bioactivity. Disease-specific applications in Alzheimer's disease, Parkinson's disease, spinal cord injury, and brain tumors are discussed in a balanced manner, with clear differentiation between preclinical findings and clinically validated evidence. Current limitations related to mechanical robustness, batch-to-batch variability, and regulatory scalability are critically evaluated, alongside emerging solutions such as surface functionalization, hybrid biomaterials, and advanced fabrication strategies. Overall, this review provides a realistic and integrative framework for understanding the opportunities and constraints of alginate-based systems in CNS therapy, emphasizing that while alginate offers significant preclinical promise, substantial translational challenges remain before widespread clinical adoption can be achieved.