Targeting the Brain: Are Nanodrugs Ready for Clinical Translation in CNS Disorders?

Although significant progress has been made in nanotechnology, the clinical translation of central nervous system (CNS) therapeutics has been limited. While engineered nanocarriers have greatly enhanced blood-brain barrier (BBB) transport, there is now growing evidence that enhanced brain delivery is not sufficient for therapeutic success. Based on this, it is suggested that the key obstacle to translation is now the poor engagement of the molecule at the BBB, its intracellular pharmacology, and its pharmacodynamic response. This perspective underscores the evolving paradigm shift from delivery-based nanomedicine to target-based precision pharmacology where therapeutic engagement is quantified by target occupancy, pathway modulation in the context of disease, and translational relevance to the human condition. This integration of validated disease biology and intelligent delivery design can now be achieved through the advent of new technologies such as artificial intelligence (AI), systems pharmacology, receptor-guided engineering of nanocarriers, spatial multi-omics, brain organoids, and BBB-on-chip technologies. This target-oriented approach is expected to facilitate clinical reproducibility and accelerate the development of safer, more effective, and individualized nanotherapeutics for CNS diseases.