Targeting Transferrin Receptor 1 for Enhancing Drug Delivery Through the Blood–Brain Barrier for Alzheimer’s Disease

Drug delivery to the brain faces a critical obstacle in the form of the blood-brain barrier (BBB), which severely limits therapeutic options for Alzheimer's disease (AD). Transferrin receptor 1 (TfR1) is abundantly expressed in brain capillary endothelial cells, offering a potential pathway for circumventing this barrier. Physiologically, TfR1 binds to iron-laden transferrin, leading to cellular uptake through clathrin-mediated endocytosis. Within acidic endosomes, the iron is released, and the receptor-apotransferrin complex recycles to the cell surface for further rounds of transport. Furthermore, studies in AD mouse models have demonstrated that TfR1 expression in brain microvessels remains stable, highlighting its suitability as a delivery target even in disease conditions. Based on this, various drug delivery strategies targeting TfR1 have been developed, including bispecific antibodies, antibody fragments, ligand conjugates, and nanoparticle-based carriers. While these approaches hold great promise, they face practical limitations such as competition with endogenous transferrin, receptor saturation, and inefficient intracellular trafficking. This review details the current understanding of TfR1-mediated BBB transport mechanisms, evaluates emerging delivery platforms, and argues that TfR1 represents an accessible gateway for brain-targeted therapeutics in AD. The insights presented will be of interest to researchers in molecular biology, pharmacology, and drug development.