Alzheimer's disease (AD) is a significant global health challenge with no cure and limited treatment options. With the growing global ageing of the population and no effective treatment, AD incidence and prevalence are expected to double in Europe by 2050. The central clinical challenge remains developing a reliable, safe, and effective therapeutic option to halt disease progression and prevent cognitive failure. Understanding AD pathogenesis and identifying targets to prevent, halt, or cure it is a top priority for the global research and medical communities. Aiming to improve AD pathophysiology, our team is developing an innovative solution to modulate the process of amyloid-ß clearance through the brain's protective barrier, i.e., the blood-brain barrier (BBB). We are developing a pioneering gene therapy that integrates CRISPR/Cas9 technology to modulate the expression of a key intervenient in amyloid-ß clearance at the BBB, thus enabling the transport of amyloid-ß across the BBB. This innovative strategy not only leverages the precision CRISPR/Cas9 but also incorporates the use of super-selective nanocarriers to target BBB and enhance the targeted delivery of therapeutic genes. By synergistically combining advanced genetic and nanotechnology strategies, our approach is anticipated to influence AD progression positively. Here, we will present our latest in vitro findings. Our results show a successful modulation of target gene expression levels in brain endothelial cells – a critical step in our intervention – and a consequent significant improvement in amyloid-ß transcytosis through the brain endothelium. These results emphasise the potential efficacy of our approach to address AD pathology.