Aptamer-Functionalized ZIF-8 Nanoscale Platform Codelivering Sorafenib and GPX4 siRNA for Targeted Osteosarcoma Therapy

Osteosarcoma remains a highly aggressive primary bone malignancy, and its clinical treatment is frequently limited by chemoresistance, systemic toxicity, and insufficient tumor-specific drug accumulation. To address these challenges, we developed an OS-7.9 aptamer-functionalized ZIF-8 nanoscale platform for the targeted codelivery of sorafenib (SFN) and GPX4 siRNA, designated O-SR-ZIF-8, with the intended application of ferroptosis-based osteosarcoma therapy. The resulting nanoparticles exhibited a uniform nanoscale size distribution, favorable colloidal stability, high payload-loading capacity, and pH-responsive release behavior. The ZIF-8 nanostructure remained relatively stable under physiological conditions but promoted accelerated release of SFN and GPX4 siRNA in acidic tumor-mimicking microenvironments, supporting its suitability for tumor-localized delivery. Compared with nontargeted formulations, O-SR-ZIF-8 markedly enhanced cellular internalization in MG-63 osteosarcoma cells, inhibited cell proliferation, promoted cell death, increased intracellular oxidative stress, and suppressed migration and invasion. In a murine osteosarcoma xenograft model, systemic administration of O-SR-ZIF-8 significantly restrained tumor growth through GPX4 silencing and modulation of ferroptosis-related signaling. Moreover, the nanoscale formulation exhibited favorable biocompatibility, as evidenced by negligible hemolytic activity and no obvious histopathological injury in major organs. Together, these findings indicate that O-SR-ZIF-8 is an aptamer-guided nanoscale therapeutic platform with potential in the treatment of osteosarcoma through targeted delivery of sorafenib and GPX4 siRNA to silence genes and increase oxidative stress associated with ferroptosis.