Chrono-Nanomedicine at the Barrier: Circadian Rhythms Influence the Delivery of Donepezil Across the BCSFB.

To reach the target tissue within the central nervous system (CNS), drugs, such as donepezil (DNPZ), must overcome naturally occurring barriers. Despite its substantial pharmacological relevance, the blood-cerebrospinal fluid barrier (BCSFB) remains insufficiently studied. The BCSFB harbors a functional molecular clock that regulates, for instance, the expression of membrane transporters. Thus, there has been an increasing interest in exploring chronotherapeutic strategies to enhance cerebral drug delivery. Additionally, nanotechnology constitutes a well-established approach for improving tissue-specific drug bioavailability within the CNS through, for example, the employment of chitosan (CS)-based nanosystems. Given the considerable potential of both approaches for the treatment of neurological disorders, we propose establishing an integrated chronotherapy-nanotechnology platform to optimize pharmacological regimens. In this context, this study aims to explore the influence of circadian rhythms in the transport of free and encapsulated DNPZ forms across an in vitro model of the BCSFB. We developed and characterized CS-based nanoparticles with promising properties for the enhanced delivery of DNPZ across brain barriers. We found that free and encapsulated drug forms of DNPZ display distinct patterns of circadian trafficking across BCSFB. In summary, our findings represent an important step toward the integration of chronotherapy and nanotechnology as a promising strategy to optimize therapeutic outcomes.