Prospects for Combination Drug Development in Central Nervous System Disorders：From Multi-target Synergy to Personalized Precision Therapy

The development of therapeutics for central nervous system （CNS） disorders is markedly lagging behind other disease areas，characterized by an exceptionally high failure rate in late-stage clinical trials. This review addresses the central challenge of creating effective combination therapies for complex CNS diseases，where single-target agents often fall short. We propose a shift from traditional empirical methods towards a rational design paradigm and explore three key enabling strategies. First，we discuss modernizing Traditional Chinese Medicine （TCM） formulations by applying multi-omics and artificial intelligence to deconvolute their multi-component，multi-target mechanisms，thus transforming them into a source for rational drug combination discovery. Second，we highlight the role of stimuli-responsive nanocarriers in achieving spatiotemporally controlled drug delivery，which allows for targeted and sequential drug release in response to the dynamic disease microenvironment. Finally，we examine how large-scale biomedical data and patient subtyping can inform the development of personalized combination regimens. Integrating these approaches，from deciphering ancient formulations to deploying advanced delivery systems and leveraging big data，presents a promising path to accelerate the development of effective，rationally designed combination therapies for CNS diseases.