Metal-Coordination Spherical Nucleic Acid Combining Antisense Oligonucleotides and Gemcitabine for Chemo–Gene–Chemodynamic Tumor Therapy

To enhance the stability of spherical nucleic acids (SNAs) and broaden the co-delivery of multiple drugs based on SNAs, we developed a multifunctional metal-coordination SNA combining antisense oligonucleotides and chemotherapeutic drugs for chemo-gene-chemodynamic therapy. This nanoplatform was prepared by a one-step metal-coordination self-assembly of nucleic acids and chemotherapeutic drugs, followed by modification with the targeting reagent folic acid. The nanoplatform showed high loading efficiency for nucleic acids and chemotherapeutic drugs with enhanced stability and resistance to interference. The antisense nucleic acids were labeled with fluorophores, which enabled easy visualization of intracellular nanodrugs. The nanoconjugates were more effectively internalized by cells than free drugs. Moreover, this nanoplatform exhibited strong activity in regulating target gene expression and inducing severe apoptosis and necrosis, and demonstrated favorable antitumor effects both in vivo and in vitro. Metal-coordination self-assembly provides up a versatile strategy for SNA-based co-delivery of nucleic acids and chemotherapeutic agents. It shows great potential for cell-specific targeting and enhanced combination therapy of tumors, which made the nanoplatform attractive for biomedical applications.