Abstract: The blood-brain barrier (BBB) is a semi-permeable biological barrier between brain tissue and plasma, however, its physical, enzymatic and immune properties, as well as its unique transport mechanism severely limit the entry of therapeutic drugs and diagnostic agents into the brain, which poses great challenges for the prevention and treatment of brain diseases. Hence, this review summarizes and discusses the complex structural components and various transport mechanisms of BBB, and interprets the difficulties and feasible ways of drug delivery across BBB. Furthermore, the latest research progress and future development trends of various delivery systems for brain drug delivery are introduced and discussed to provide references for further perfecting their design and driving their transformation. Finally, this review discusses the pathological changes of BBB in brain diseases and the design of drug delivery strategies for pathological BBB. Collectively, this review highlights the design and optimization of drug delivery strategies across the BBB based on nano-delivery system and provides accessible guide for current opportunities and challenges of intracerebral drug delivery.