Hierarchical Precision Nanoplatform for Synergistic Radio-Immunotherapy in Glioblastoma via Controllable P-Selectin Targeting

The combination of radiotherapy and immune checkpoint blockade (ICB) therapy has demonstrated considerable efficacy in oncological treatment. However, the clinical PD-L1 antibody (anti-PD-L1) for glioblastoma (GBM) imprecisely accumulated in intracranial radiotherapy target and is often compromised by the formidable blood-brain barrier (BBB). To address these challenges, the study innovatively engineers a hierarchical precision delivery nanoplatform (FB-aPD-L1). This nanoplatform leverages sulfated fucoidan, which exhibited targeted affinity for P-selectin, an adhesion molecule expressed with spatiotemporally restricted specificity in response to radiotherapy. Following precise capture FB-aPD-L1 and crossing BBB, there is ultrasensitive release of BPA₄-aPD-L1 and fucoidan in the tumor microenvironment. The targeted conjugation of 5-borono-2-pyridinecarboxylic acid (BPA) and sialic acid (SA) augmented tumor-specific targeting and retention of anti-PD-L1, while fucoidan reprogrammed the immune microenvironment, thereby synergizing with the anti-PD-L1 to increase CD8⁺ T cell infiltration and enhance radio-immunotherapy efficacy. This work exemplifies a novel paradigm for brain-targeted precise drug delivery.