Gene-based Nanotherapeutics and Precision Delivery Strategies in Alzheimer's Disease

Introduction: Alzheimer’s disease (AD) is the leading cause of dementia worldwide, characterized by amyloid-β accumulation, tau hyperphosphorylation, neuroinflammation, and synaptic dysfunction. Current pharmacological options offer only symptomatic relief, without altering the disease progression. Methods: This review explores evidence from preclinical and clinical studies on gene-based nanotherapeutic approaches and precision delivery systems in AD. Literature was gathered from PubMed, Scopus, Web of Science, and Google Scholar, focusing on gene-silencing strategies and innovative nanocarrier technologies. Results: Gene-based interventions such as siRNA, mRNA, and antisense oligonucleotides target key pathogenic proteins, including APP, BACE1, tau, and α-synuclein. Nanocarrier systems, lipid nanoparticles, extracellular vesicles, cell-penetrating peptides, and ROS-responsive micelles improve blood-brain barrier penetration and therapeutic efficacy. Non-invasive delivery methods, including intranasal administration and focused ultrasound-mediated BBB disruption, enhance localized targeting while minimizing systemic toxicity. Several candidates, such as BACE1 siRNA-loaded nanoparticles and antisense peptide conjugates, demonstrated significant reduction in amyloid burden, tau pathology, and cognitive deficits in animal models. Industrial pipelines show a clear transition from symptomatic management toward disease-modifying therapies, with multiple candidates in advanced clinical phases. Discussion: The convergence of nanotechnology and gene therapy represents a paradigm shift in AD management. While preclinical results are promising, clinical translation faces challenges related to safety, long-term efficacy, large-scale manufacturing, and regulatory hurdles. Conclusion: Gene-based nanotherapeutics combined with precision delivery strategies hold strong potential to transform AD treatment from palliative to disease-modifying. Future success will depend on interdisciplinary collaboration, patient-centered delivery systems, and accelerated clinical validation.