Critical Challenges of Intravenous Nanomaterials Crossing the Blood‐Brain Barrier: from Blood to Brain

Abstract Despite recent advancements in the development of blood‐brain barrier (BBB)‐crossing nanomaterials for intravenous administration, there have been very few successful cases in clinical trials. Ongoing challenges within the body impede the precise therapeutic effects of these nanomaterials from reaching their intended target area. Therefore, a comprehensive analysis of the entire pathway that BBB‐crossing nanomaterials must traverse‐from the bloodstream to the brain‐along with an understanding of the obstacles encountered along the way, is essential for advancing these materials to clinical trials. This review begins with a brief overview of the structure and function of the BBB, as well as the pathways and strategies for crossing it. Next, it is discussed and analyzed the common challenges that BBB‐crossing nanomaterials in reaching their target sites in the brain from the bloodstream. To address these challenges, an “eight‐step” guideline strategy is proposed. By leveraging the principles of precision medicine, the design and customization of cascade‐targeted BBB‐crossing nanomaterials that can overcome multiple obstacles show promise for future clinical trials and practical applications. Finally, a perspective on the future direction of this field is offered.