Pathology-directed drug delivery strategies: How to overcome blood–brain barrier for the treatment of brain diseases

Despite the different degrees of blood–brain barrier (BBB) damage in diverse brain diseases, it remains a formidable barrier that restricts most drugs from penetrating the brain. A comprehensive understanding and elucidation of the disease-specific changes of BBB in various brain pathologies are essential for directing the customized brain-targeted drug delivery systems, potentially improving cerebral delivery efficiency and therapeutic efficacy. Hence, this review compared anatomical and physiological changes of BBB under healthy and pathological states and discussed the effects of these changes on cerebral delivery efficiency. Thereafter, a particular emphasis was placed on the pathology-directed drug delivery strategies tailored to different brain diseases, including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, stroke, and brain tumors. By combining insights from cutting-edge studies and emerging technologies, we proposed forward-looking suggestions on future directions to brain-targeted drug delivery, thereby improving the therapeutic efficacy and accelerating the translation from preclinical attempts into clinical practice. We reviewed the changes in structure and function of blood–brain barrier (BBB), summarized and discussed the unique pathological features and corresponding pathology-directed brain-targeted drug delivery systems in different brain diseases.