Brain-Targeting siRNA Delivery to Tackle Alzheimer's Disease.

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that places an increasing burden on patients, caregivers, and healthcare systems worldwide. Current disease-modifying therapies (DMTs) are limited by high costs, complex administration, and reliance on advanced biomarker infrastructure, highlighting the shortcomings of existing treatment paradigms. These limitations have sparked growing interest in gene- and nucleic acid-based interventions as upstream strategies to modify AD pathogenesis. Among these, small interfering RNA (siRNA) is especially compelling because it can be rationally programmed, directed at multiple molecular pathways, and paired with rapidly evolving delivery technologies. However, the clinical translation of siRNA therapies for AD is still constrained by challenges in brain-targeted delivery, safety, and sustained efficacy. In this review, we summarize current concepts in AD pathology, highlight recent clinical and translational advances, and critically assess emerging brain-targeted siRNA delivery platforms and their key bottlenecks. Within a precision-medicine framework, brain-targeted siRNA offers the possibility of aligning patient selection, molecular targets, and delivery strategies with biomarker-defined AD endotypes. We discuss both the therapeutic promise and the realistic limitations of siRNA-based approaches for AD, outline priorities for future development, and identify key gaps that must be addressed to enable meaningful clinical implementation.