Trojan Horse Strategies for Nose-to-Brain Drug Delivery: Exploiting Biological Uptake Mechanisms Beyond the Blood-Brain Barrier

The delivery of therapeutic agents to the central nervous system (CNS) remains a major challenge due to the restrictive nature of the blood–brain barrier (BBB), which limits the penetration of most small molecules and biologics. Conventional systemic approaches often fail to achieve adequate brain concentrations while increasing the risk of systemic toxicity. In response to these limitations, Trojan horse strategies have emerged as a promising approach to facilitate drug transport across the BBB by exploiting endogenous transcytosis mechanisms. These strategies primarily rely on receptor-mediated transcytosis and adsorptive-mediated transcytosis pathways, enabling nanocarriers to mimic physiological substrates and gain controlled access to the brain. Recent advances in nanotechnology have enabled the design of polymeric nanoparticles, lipid-based carriers, mesoporous silica systems, and vesicular nanoplatforms capable of integrating targeting ligands, charge modulation, and stimulus-responsive elements to enhance BBB transport efficiency. In parallel, the intranasal route has attracted increasing attention as a non-invasive alternative for brain delivery by bypassing vascular barriers through olfactory and trigeminal neural pathways. The convergence of Trojan-horse targeting principles with nose-to-brain delivery strategies represents a promising paradigm for improving CNS drug delivery. However, several translational challenges remain, including receptor saturation, mucociliary clearance, variability in nasal deposition, safety concerns, and large-scale manufacturing limitations. This review provides a comprehensive overview of the biological basis of BBB transport, the mechanistic principles underlying Trojan-horse nanocarriers, and emerging nanotechnological strategies designed to enhance nose-to-brain drug delivery. Understanding the interplay between nanoparticle physicochemistry, endothelial transport mechanisms, and nasal anatomical pathways will be essential for advancing Trojan-based systems toward clinically viable brain-targeting therapies.