A new route across the blood-brain barrier

A new route across the blood-brain barrier

Here, Cedars-Sinai Medical Center discusses crossing the blood–brain barrier (BBB), a defining challenge in the development of effective therapies. Crossing the blood–brain barrier (BBB) remains a defining challenge in the development of effective therapies for brain diseases and brain metastases, with most nanomedicine strategies constrained to a narrow set of canonical transport pathways that have delivered limited clinical success. Here we highlight key findings from our Nature Nanotechnology (2025) study which introduces HER3 (ErbB3) as a previously unrecognized BBB transport receptor and demonstrates that HER3 targeted nanobioparticles can exploit this pathway to achieve efficient, non disruptive brain entry while preserving cargo integrity. Using human blood–brain barrier on chip platforms, HER3 mediated transport is shown to proceed via caveolae associated transcytosis in endothelial cells, in contrast to HER3 directed endocytic routing in tumor cells that enables endosomal escape and cytoplasmic cargo release. Together, these findings establish a new paradigm for brain delivery—one in which a single, biologically validated targeting strategy supports both BBB traversal and effective tumor engagement within the brain, with strong human relevant translational confidence.