Osteosarcoma is a primary malignant bone tumor with elevated mortality rates in youngsters and adolescents. Current therapeutic approaches entail preliminary chemotherapy followed by surgical removal and supplementary chemotherapy. Roughly 30% of patients experience recurrence, underscoring the limitations, as surgery alone cannot effectively manage metastasis. Nanoparticle-mediated targeted drug delivery systems present a promising therapeutic avenue for osteosarcoma, as they overcome the constraints of conventional chemotherapy by augmenting retention, permeability, and active targeting. Objectives Devise and construct systemic drug co-delivery systems by utilizing nanoscale modification of miR-34a and doxorubicin via layer-by-layer (LbL) assembly for precise osteosarcoma treatment. Approaches PLGA-CS polyplexes were produced using optimized nano-complexation and LbL assembly techniques.