Engineering a Biodegradable Nanocarrier for Enhancing the Response of T98G Cells to Temozolomide

Temozolomide (TMZ), the most common DNA alkylating agent, is predominantly mediated by O⁶-methylguanine DNA lesions for the treatment of glioblastoma (GBM). When O⁶-methylguanine-DNA methyltransferase (MGMT) is present, TMZ-induced O⁶-methylguanine lesions are repaired, resulting in the emergence of resistance to chemotherapy. Herein, we attempted to enhance the response of T98G cells to TMZ by gene silencing of MGMT. In this work, we developed transition metal manganese (Mn)-doped mesoporous silica nanoparticles (MSNs) as a carrier system for the co-delivery of TMZ and 10-23 DNAzyme, and realized gene silencing to enhance the TMZ sensitivity in T98G cells. The intelligent theranostic platform based on manganese-doped mesoporous silica nanoparticles (Mn-MSNs) can be decomposed and release chemotherapy drugs under acidic pH and reducing conditions. Meanwhile, the produced Mn²⁺ could act as a cofactor of 10-23 DNAzyme to effectively cleave MGMT mRNA, knock down MGMT protein, and sensitize T98G cells to TMZ-induced apoptosis. By co-delivering TMZ and 10-23 DNAzyme employing Mn-MSNs, the concentrations of TMZ that needed to inhibit cell growth by 50% (IC₅₀ values) decreased (by more than 3.8-fold) compared with free TMZ. This work shows that the designed platform holds great promise for advancing the treatment of drug-resistant cancer.