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

Abstract 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 BPA ₄ ‐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.