Targeting tumour-neuron synapses with intracavitary RNA delivery prevents glioblastoma recurrence.

Tumour-neuron interactions and malignant synapse formation drive glioblastoma progression, recurrence and neurological dysfunction, but systemic inhibition of synaptic signalling causes unacceptable neurotoxicity. Here we defined the spatial and molecular determinants of malignant synapses by analysing intact human glioblastoma specimens, revealing enrichment of synapse-like structures and synapse-associated gene programmes at the tumour-brain interface. Spatial and transcriptomic analyses highlighted the neurotrophic receptor TrkB as a candidate therapeutic target at the tumour-brain interface. Guided by this target, we developed an intracavitary, multiresponsive hydrogel that locally delivers small interfering RNA to silence TrkB in residual tumour cells after surgery. In syngeneic and patient-derived glioblastoma models, treatment suppressed tumour regrowth and prolonged survival; in the syngeneic GL261 model, median survival increased from 32 to 67 days, with more than 30% of treated animals surviving beyond 90 days. TrkB silencing reduced excitatory synaptic input to tumour cells and alleviated tumour-associated anxiety and memory deficits without impairing motor function. Combination with radiotherapy further reduced invasive growth at the tumour-brain interface and extended survival. Together, these findings establish a spatially restricted, mechanism-guided therapeutic strategy for glioblastoma.