Rethinking CRITID Procedure of Brain Targeting Drug Delivery: Circulation, Blood Brain Barrier Recognition, Intracellular Transport, Diseased Cell Targeting, Internalization, and Drug Release

The past decades have witnessed great progress in nanoparticle (NP)‐based brain‐targeting drug delivery systems, while their therapeutic potentials are yet to be fully exploited given that the majority of them are lost during the delivery process. Rational design of brain‐targeting drug delivery systems requires a deep understanding of the entire delivery process along with the issues that they may encounter. Herein, this review first analyzes the typical delivery process of a systemically administrated NPs‐based brain‐targeting drug delivery system and proposes a six‐step CRITID delivery cascade: circulation in systemic blood, recognizing receptor on blood‐brain barrier (BBB), intracellular transport, diseased cell targeting after entering into parenchyma, internalization by diseased cells, and finally intracellular drug release. By dissecting the entire delivery process into six steps, this review seeks to provide a deep understanding of the issues that may restrict the delivery efficiency of brain‐targeting drug delivery systems as well as the specific requirements that may guarantee minimal loss at each step. Currently developed strategies used for troubleshooting these issues are reviewed and some state‐of‐the‐art design features meeting these requirements are highlighted. The CRITID delivery cascade can serve as a guideline for designing more efficient and specific brain‐targeting drug delivery systems.