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In particular, in TfR-targeted systems, excessively high-affinity binding may create a binding-site barrier, leading to preferential endothelial retention and intracellular sequestration rather than productive transcytosis across the BBB (Pinkiewicz et al., 2025), while lysosomal trapping may degrade internalized cargo before abluminal release, while lysosomal trapping may degrade internalized cargo before abluminal release (Salimi et al., 2023)
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