Synergistic effect of Yes-associated protein siRNA and temozolomide against glioblastoma using a localized nano...

Glioblastoma is the most aggressive type of brain tumor. Localized chemotherapy in combination with gene silencing may be an effective treatment approach. Herein, we developed a localized delivery system using trimethyl chitosan-hyaluronate composite nanoparticles of temozolomide and YAP-siRNA (TMZ + siRNA@NPs) loaded in gelatin methacrylate (GelMA)/Alginate hydrogel to potentiate the inhibition of tumor growth. The fabricated hydrogel subjected for mechanical and physical behaviors characterization. Achieving efficient encapsulation of both TMZ, a hydrophobic drug, and YAP-siRNA, which is hydrophilic, in a single nanoparticle system requires careful optimization. The nanoparticles were spherical, with a size of 101 ± 4.3 nm and an entrapment efficiency of 79.28 ± 6.1 % for TMZ. The YAP-siRNA was efficiently retarded by NPs. The controlled and pH-dependent release patterns of TMZ from the NPs and hydrogel were confirmed. Combination therapy with TMZ + siRNA@NPs resulted in the lowest IC₅₀ values in glioma cell lines with efficient in-vitro YAP knockdown at mRNA and protein levels. In-vivo antitumor study revealed the smallest tumor volume in the Hydrogel/TMZ + siRNA@NPs group with increased apoptosis, potent anti-proliferative effects, and 51.73 % YAP downregulation. In conclusion, this localized combination therapy with TMZ and YAP-siRNA represents a promising approach against glioblastoma with strong apoptotic and tumor growth inhibitory effects.