Hijacking radiotherapy-induced chemokines with self-assembled molecular decoys for glioblastoma radio-immunotherapy.

Glioblastoma (GBM) management is critically impeded by the blood-brain barrier (BBB) and acquired radioresistance. To overcome these hurdles, we engineered a genetically modified biomimetic "nanosponge" (CCR2@VCNPs) designed to synergistically sensitize radiotherapy (RT) and remodel the tumor microenvironment. The nanoplatform consists of a self-assembled core composed of Verteporfin and Celecoxib (VCNPs), which provides high drug loading capacity and enables coordinated delivery of both agents. By cloaking this self-assembled core with membranes derived from macrophages overexpressing CC chemokine receptor 2 (CCR2), the nanoparticles achieve dual-mode targeting: mimicking leukocyte-endothelium interactions for BBB transcytosis and exploiting the CCL2/CCR2 axis for active chemotactic navigation. Notably, the surface CCR2 serves as a "molecular decoy" to intercept RT-induced CCL2, effectively blocking the infiltration of immunosuppressive myeloid cells. Upon tumor accumulation, the self-delivered Verteporfin acts as a potent radiosensitizer by generating singlet oxygen and inhibiting the YAP/TAZ pathway, while Celecoxib (CXB) concurrently abrogates RT-induced immunosuppression by disrupting the COX-2/PGE2 signaling axis. This integrated strategy promotes robust immunogenic cell death (ICD), effectively transforming the "cold" GBM niche into a "hot" immunological phenotype. In orthotopic GBM mouse models, CCR2@VCNPs significantly prolonged median survival and suppressed orthotopic tumor progression. By integrating molecular self-assembly with genetic membrane engineering, this strategy offers a comprehensive solution to therapeutic resistance and shows translation potential for clinical GBM management.