DNA hydrogels for glioblastoma: programmable, tumor-responsive nanocarriers for precision therapy and theranostics

Glioblastoma (GBM) is the most lethal primary brain tumor, with median survival of only 12–18 months despite maximal surgery, radiotherapy, and chemotherapy. Its infiltrative growth, molecular heterogeneity, and therapy resistance, compounded by the restrictive blood–brain barrier (BBB), severely limit conventional treatments, highlighting an urgent need for precision-targeted, clinically translatable therapies. DNA hydrogels have emerged as a next-generation nanomedicine platform with exceptional programmability, biocompatibility, and stimuli-responsive properties. They can be engineered to respond to tumor microenvironmental cues—such as acidic pH, enzymatic activity, and hypoxia—triggering localized, controlled drug release. Functionalization with BBB-targeting ligands and tumor-specific moieties enhances selective delivery, while modular architectures support multi-drug loading, combination therapy, and theranostic integration. Emerging innovations, including hybrid DNA hydrogel–nanoparticle composites and multi-stage release systems, offer unprecedented opportunities for synergistic chemotherapy, immunomodulation, radiotherapy sensitization, and real-time therapeutic monitoring. By combining efficacy, safety, and translational feasibility, DNA hydrogels address critical challenges in GBM management. This review discusses the design, functional properties, and therapeutic applications of DNA hydrogels in glioblastoma, emphasizing clinically actionable strategies, translational considerations, and future perspectives. Harnessing DNA hydrogels as smart, multifunctional nanocarriers has the potential to transform GBM therapy, empowering clinicians with precision-guided, adaptive interventions that improve survival and patient quality of life.