A dual-ligand PAMAM nanocarrier (L57&PGP-PEG-PAMAM) employing a 'cross-and-capture' strategy sequentially traverses the BBB via LRP1-mediated transcytosis and anchors within the ischemic inflammatory microenvironment via CXCR2-targeted neutrophil capture, reducing infarct volume and improving neurological outcomes in a rat MCAO model.
The dual-targeting nanocarrier L57&PGP-PEG-PAMAM exhibited a hydrodynamic diameter of 140.2 ± 0.6 nm with a zeta potential of 9.32 mV.
The nanocarrier achieved a breviscapine loading capacity of 20.12% and an encapsulation efficiency of 71.78%.
In vivo fluorescence imaging confirmed markedly superior brain accumulation of the dual-targeted nanocarrier relative to non-targeted and PEGylated-only controls.
In a rat MCAO model, L57&PGP-PEG-PAMAM/Bre reduced infarct volume to 21.7 ± 6.4%.
Treatment with the dual-targeted nanocarrier improved neurological scores to 1.52 ± 0.28 in the MCAO rat model.
The dual-targeted nanocarrier suppressed pro-inflammatory cytokines IL-15 and IL-27 in the MCAO rat model.
The 'cross-and-capture' strategy decouples BBB penetration from lesion-specific retention by using two functionally distinct targeting ligands.
This research suggests that a major obstacle in treating ischemic stroke is getting protective drugs past the blood-brain barrier (BBB) — the tightly regulated gateway between the bloodstream and brain — and then keeping the drug at the site of injury long enough to work. The researchers engineered a tiny drug-delivery vehicle (nanocarrier) made from a branched polymer called PAMAM, decorated with two different homing molecules: one (L57) to help it cross the BBB by hitching a ride on a natural transport protein, and another (PGP) to lock it onto immune cells (neutrophils) that flood the injury site during a stroke. This 'cross-and-capture' design loaded the neuroprotective drug breviscapine and released it slowly over 72 hours. In rats with experimentally induced stroke (MCAO model), this dual-targeted nanocarrier significantly outperformed free breviscapine and simpler nanocarrier versions. It reduced the volume of dead brain tissue to about 21.7%, improved neurological function scores, and lowered levels of two inflammatory signaling molecules (IL-15 and IL-27) that contribute to brain damage after stroke. Imaging confirmed the nanocarrier accumulated in the brain far more effectively than control formulations without the targeting molecules. This research suggests that pairing two distinct targeting strategies — one for crossing into the brain and one for staying at the injury site — could be a powerful approach for delivering stroke therapies more effectively. Because current treatments for ischemic stroke are very limited and time-sensitive, nanocarrier systems like this could potentially expand the therapeutic window and improve outcomes, though further studies including safety testing and trials in larger animals or humans would be needed before any clinical application.
Guo H, Han D, Liu X. (2026). Cross-and-Capture: A Dual-Ligand PAMAM Nanocarrier for Sequential BBB Penetration and Ischemic Lesion Retention of Breviscapine.. Molecules (Basel, Switzerland). https://doi.org/10.3390/molecules31193363