A biohybrid chiral hydrogel enhances preclinical postoperative glioblastoma therapy by multi-pronged inhibition of tumor stemness

Glioblastoma stem cells (GSCs), which exhibit resistance to multiple treatments, are a prominent driver of postoperative glioblastoma (GBM) relapse. Declining the GSC population holds promise in GBM therapy but remains challenging, due to the difficulty in orchestrating the complex cytokine signaling programs and extracellular matrix features that induce GSC expansion. Here, we develop a biohybrid chiral hydrogel that allows intracavity implantation after GBM surgical debulking to comprehensively regulate GSC stemness, enhancing postoperative therapy. The hydrogel encapsulates GSC membrane-coated nanoparticles (GSNP), which serve as potent decoys to broadly neutralizing GSC-targeted pro-stemness and chemotaxis cytokines, allowing functional blocking and hydrogel infiltration of GSCs. Moreover, we showed that the D-chiral biohybrid hydrogel (D-gel@GSNP), in contrast to its L- and DL-chiral counterparts, further diminishes GSC stemness phenotype via D-chiral geometry-regulated mechanotransduction pathways. In three orthotopic intracranial GBM models, multi-pronged inhibition of GSC stemness enhances the gold nanoclusters-based hydrogel scaffold-sensitized radioimmunotherapy, enabling suppression of GBM relapse post-resection. This integrated regulation of biochemical and biophysical cues shows potential for treating cancer stem cell (CSC)-enriched malignancies.