Influence factors on and potential strategies to amplify receptor-mediated nanodrug delivery across the blood–brain barrier

ABSTRACTIntroduction A major challenge in treating central nervous system (CNS) disorders is to achieve adequate drug delivery across the blood–brain barrier (BBB). Receptor-mediated nanodrug delivery as a Trojan horse strategy has become an exciting approach. However, these nanodrugs do not accumulate significantly in the brain parenchyma, which greatly limits the therapeutic effect of drugs. Amplifying the efficiency of receptor-mediated nanodrug delivery across the BBB becomes the holy grail in the treatment of CNS disorders.Areas covered In this review, we tend to establish links between dynamic BBB and receptor-mediated nanodrug delivery, starting with the delivery processes across the BBB, describing factors affecting nanodrug delivery efficiency, and summarizing potential strategies that may amplify delivery efficiency.Expert opinion Receptor-mediated nanodrug delivery is a common approach to significantly enhance the efficiency of brain-targeting delivery. As BBB is constantly undergoing changes, it is essential to investigate the impact of diseases on the effectiveness of brain-targeting nanodrug delivery. More critically, there are several barriers to achieving brain-targeting nanodrug delivery in the five stages of receptor-mediated transcytosis (RMT), and the impacts can be conflicting, requiring intricate balance. Further studies are also needed to investigate the material toxicity of nanodrugs to address the issue of clinical translation.KEYWORDS: Blood–brain barrier (BBB)central nervous system (CNS) disordersbrain-targeting drug deliveryreceptor-mediated transcytosis (RMT)nanodrug Article highlights Alterations in the BBB under pathological conditions can potentially affect the brain targeting delivery of nanodrugs.Multiple factors in the RMT process affect the delivery efficiency of nanodrug across the BBB.Single factor, such as ligand affinity, may have opposite effects on the delivery efficiency of the different stages of RMT and need to be carefully weighed.The correlation between BBB and CNS disorders, as well as the specific mechanism of RMT on brain endothelial cells (BECs), require further investigation.Declaration of interestThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.Reviewer disclosuresPeer reviewers on this manuscript have no relevant financial or other relationships to disclose.Additional informationFundingThe work was supported by the Research and Development Program of Science and Technology Department of Sichuan Province (2022JDJQ0050), 111 Project (B18035), and the Fundamental Research Funds for the Central Universities.