Neurodegenerative diseases (NDDs), including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis, are progressive disorders characterized by neuronal dysfunction and structural instability. Central to their pathology are aberrations in extracellular matrix (ECM) remodeling and chronic neuroinflammation, processes regulated by the ADAMTS family of metalloproteinases. Dysregulated activity of specific ADAMTS isoforms, such as ADAMTS-4 and ADAMTS-5, contributes to pathological ECM degradation, triggering neuroinflammatory cascades, synaptic disruption, and neuronal loss. This article proposes a novel therapeutic approach: the development of partial agonists targeting ADAMTS enzymes. Unlike broad-spectrum inhibitors, which can suppress essential protease functions, partial agonists offer a balanced strategy by selectively modulating enzymatic activity. These agents aim to mitigate pathological ECM degradation while preserving physiological ECM dynamics, addressing both neuroinflammation and ECM imbalance.

The design of partial agonists leverages bioisosteric principles to create isoform-specific targeting agents with high therapeutic precision. Structural scaffolds inspired by protease–substrate interactions are central to this approach. Additionally, innovative drug delivery systems, including nanoparticle encapsulation and prodrug strategies, are explored to overcome the formidable challenge of crossing the blood–brain barrier and ensure sustained drug release in the central nervous system. Advanced delivery platforms enhance therapeutic efficacy while minimizing systemic side effects, which is a critical consideration for chronic neurodegenerative disease management and therapy and developing potential curative strategies.

This research highlights the potential of ADAMTS-targeting partial agonists to transform NDD therapeutics by restoring ECM integrity and reducing neuroinflammation. Through these mechanisms, partial agonists can enhance neuronal resilience, stabilize synaptic networks, and significantly improve clinical outcomes, offering new hope for individuals affected by debilitating neurodegenerative conditions.