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

Glioblastoma stem cells (GSCs), which exhibit resistance to multiple treatments, are a prominent driver of postoperative glioblastoma (GBM) relapse. Reducing the GSC population holds promise in GBM therapy but remains challenging due to the difficulty in coordinating the complex cytokine signalling programs and extracellular matrix characteristics 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 that serve as potent decoys to broadly neutralize GSC-targeted pro-stemness and chemotaxis cytokines, allowing functional blocking and hydrogel infiltration of GSCs. Moreover, we showed that the D-chiral biohybrid hydrogel, in contrast to its L- and DL-chiral counterparts, further diminished the GSC stemness phenotype via D-chiral-geometry-regulated mechanotransduction pathways. In three orthotopic intracranial GBM models, the multi-pronged inhibition of GSC stemness enhanced gold-nanocluster-based hydrogel-scaffold-sensitized radioimmunotherapy, enabling the suppression of GBM relapse post-resection. This integrated regulation of biochemical and biophysical cues shows the potential for treating cancer-stem-cell-enriched malignancies.