Intranasal delivery of temozolomide and disulfiram in situ gel combined with copper for enhanced glioblastoma therapy

Combination therapies show promise for glioblastoma (GBM) treatment, however, insufficient drug accumulation in the brain and significant toxic side effects continue to pose critical challenges to therapeutic efficacy. Here, we report an intranasal ion-sensitive hydrogel (IHG) platform for efficient co-delivery of TMZ and disulfiram (DSF) to GBM via the nose-to-brain pathway. The optimized IHG formulation demonstrates superior gelation properties, sustained drug release, and enhanced brain accumulation, achieving remarkable drug targeting efficiency (468.9%) and direct transport percentage (80.3%). Within the tumor microenvironment, in situ-generated TMZ and the chelation product of DSF and copper ions (CuET) synergistically induce DNA damage and apoptosis, thereby enhancing tumor cell sensitivity to TMZ. Furthermore, tdIHG+Cu induces robust immunogenic cell death, stimulates CXCL10 release, mediates dendritic cell maturation, and promotes CD8 + T cell infiltration, thereby establishing a potent antitumor immune response. This approach not only demonstrates superior therapeutic efficy against GBM progression through enhanced intracranial drug accumulation and optimized drug ratios, but also minimizes systemic toxicity via localized delivery. Our findings offer a potentially clinical translatable strategy worth further investigation.