Abstract

Renal cell carcinoma (RCC) is a challenging urologic malignancy characterized by its aggressive nature, including invasion, metastasis, and treatment resistance. To explore multi-targeted therapies, we established an advanced clear cell renal cell carcinoma (ccRCC) model via orthotopic tumor transplantation in mice, and established another model simulating post-surgical recurrence by performing radical nephrectomy. We engineered a genetic circuit to reprogram the host liver as a bioreactor, enabling the production and delivery of in vivo self-assembled siRNAs (IVSA-siRNAs) for co-targeting VEGFR2 and mTOR . The efficacy and toxicity of this IVSA-siRNA system were evaluated and compared with the combination therapy of sunitinib and everolimus. In the established models, the combination therapy of sunitinib and everolimus showed efficacy but induced severe adverse effects. In contrast, IVSA-siRNAs potently silenced VEGFR2 and mTOR expression, achieving therapeutic effects in both advanced and radical nephrectomy ccRCC models without discernible toxicity.