Degenerative disorders of the central nervous system (CNS), such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) and amyotrophic lateral sclerosis (ALS), lead to progressive neuronal loss and remain incurable. Current pharmacotherapies provide symptomatic treatment rather than addressing the underlying pathology and do not repair damaged neural networks. A major bottleneck is the blood-brain barrier (BBB), which protects the brain from toxins but also restricts the entry of most drugs. As a result, many promising compounds fail to reach diseased neurons. This narrative review surveys recent advances in nanotechnology, biomaterials and tissue engineering that seek to overcome the BBB and promote neural regeneration. Particular emphasis is given to multiscale nanocomposite scaffolds that mimic the architecture of the extracellular matrix (ECM) and respond to microenvironmental cues to deliver drugs or bioactive molecules in a controlled manner .Multifunctional scaffolds embedded with smart nanocarriers enable highly localized drug delivery, and simultaneously provide structural and biochemical cues that favor neuronal growth. Hierarchical architectures fabricated from natural, synthetic or hybrid polymers mimic the ECM and support cell adhesion and differentiation. Multiscale and stimuli-responsive nanocomposite scaffolds represent a promising convergence of drug delivery, regenerative medicine and mechanobiology. Their success will depend on rational design based on mechanistic understanding, integration of living cells and biologics, as well as careful tuning of material properties to the neural microenvironment. Neurodegenerative diseases (AD, PD, HD, ALS) impose a heavy global burden, with current treatments only providing symptomatic relief and facing Blood-Brain-Barrier penetration barriers; multiscale stimuli-responsive nanocomposite scaffolds—integrating BBB-crossing drug delivery, biomimetic repair structures, and living composite systems—have shown positive preclinical outcomes such as improved cognitive/motor function and neural regeneration, yet face translational hurdles including biosafety, manufacturing scalability, clinical validation, and regulatory complexities, with future efforts focusing on personalized medicine, 4D scaffolds, and multimodal integration to enhance therapeutic effects.
Chen et al. (Thu,) studied this question.