An integrative neuropharmacological review of Huntington's disease challenges and the role of novel formulations in addressing pharmacological‒pharmaceutical limitations.

Background: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by CAG repeat expansion in the huntingtin gene, leading to progressive neuronal dysfunction and neurodegeneration. Although classically defined as a brain-restricted disorder marked by striatal and cortical degeneration, increasing evidence suggests HD as a multisystem disease involving both central and peripheral pathological alterations. Objective: This review aims to provide an integrated overview of neuronal and non-neuronal mechanisms underlying HD, focusing on systemic alterations that influence disease onset, progression, and clinical variability. This review also aims to connect neuropharmacology with pharmaceutical formulation strategies, particularly emphasizing the therapeutic and drug-delivery challenges and nanotechnology-based solutions. Methods: A structured literature review was conducted using databases including PubMed, EMBASE, and Scopus. Using the appropriate keywords, original articles, clinical studies, systematic reviews, meta-analyses, and high-quality reviews were selected based on their relevance to HD pathophysiology and therapeutic strategies. Results: HD manifests with motor, cognitive, and psychiatric disturbances; however, this review highlights that peripheral immune activation, gut microbiota dysbiosis, and multiorgan pathology are not merely secondary features but interact with neural circuits, contributing to disease heterogeneity and progression. Current therapeutic approaches are largely symptomatic, achieving minimal effectiveness in disease modification due to challenges such as poor blood-brain barrier penetration, limited target selectivity, and inter-individual variability. New strategies, such as nanotechnology-based drug delivery systems, biologics, and gene editing tools, offer advantages and support a deeper understanding of therapeutic limitations and disease mechanisms, yet their translational applicability remains constrained by limited clinical validation, safety concerns, and scalability problems. Conclusion: Reconceptualizing HD as a multisystem disorder provides a more comprehensive framework for therapeutic development. Integrating central and peripheral disease mechanisms with advances in targeted drug delivery and patient stratification approaches, such as sex differences, hormonal influences, and environmental factors, is essential for translational progress toward personalized therapeutic approaches. Future research should prioritize interdisciplinary approaches to bridge the gap between mechanistic discoveries and effective disease-modifying interventions.