Cross-and-Capture: A Dual-Ligand PAMAM Nanocarrier for Sequential BBB Penetration and Ischemic Lesion Retention of Breviscapine.

The clinical management of ischemic stroke is severely constrained by the blood-brain barrier (BBB), which restricts therapeutic drug access to the brain parenchyma, and the rapid systemic clearance of neuroprotective agents such as breviscapine (Bre). To overcome this dual challenge, we engineered a dual-targeting nanocarrier, L57&PGP-PEG-PAMAM, designed to sequentially traverse the BBB and anchor within the ischemic inflammatory microenvironment. This construct employs a PEGylated fifth-generation polyamidoamine (PAMAM) dendrimer scaffold functionalized with two distinct peptides: L57, which mediates transcytosis via LRP1 receptors on the BBB, and PGP, which targets CXCR2 receptors overexpressed on infiltrating neutrophils at the lesion. The resulting nano particles exhibited a hydrodynamic diameter of 140.2 ± 0.6 nm (zeta potential: 9.32 mV) and encapsulated Bre with a loading capacity of 20.12% and encapsulation efficiency of 71.78%, displaying sustained release (54.6% over 72 h). Crucially, in vivo fluorescence imaging confirmed markedly superior brain accumulation relative to non-targeted and PEGylated-only controls, while in a rat MCAO model, the formulation reduced infarct volume to 21.7 ± 6.4%, improved neurological scores to 1.52 ± 0.28, and suppressed pro-inflammatory IL-15/IL-27 levels-collectively outperforming free Bre. This work establishes a robust "cross-and-capture" strategy that effectively decouples BBB penetration from lesion-specific retention for ischemic stroke therapy.