The main objective of this project is to develop an innovative nanotherapy modality by combining platinum Pt chemotherapy and MYC-targeting RNA interference RNAi for more effective treatment of metastatic prostate cancer PCa. In Year 2 of this project, we have made substantial accomplishments for the proposed tasks. We systematically evaluated the in vivo behaviors e.g., PK and BioD of the NP platform PDSA8-2 NPs optimized in Year 1 of this project. The optimal NPs showed long blood circulation, and can efficiently deliver siRNA to PCa tumor tissues to inhibit MYC expression. We showed that the NP-mediated MYC silencing could significantly inhibit tumor growth in PCa xenograft model. We also successfully established Pt-resistant PCa cells and investigated the in vitro toxicity of the NPs loaded with MYC siRNA and cisplatin prodrug synthesized in Year 1 of this project against the Pt-resistant PCa cells. In parallel, we further characterized the phenotypic characteristics of the cell lines derived from sites of metastasis of MYC-driven transgenic BMPC tumors established in Year 1 of this project, and employed the new cell line to evaluate the in vitro and in vivo MYC silencing by the optimal NPs. We demonstrated that the NP-mediated MYC silencing can significantly inhibit the proliferation of BMPC cells. We also did RNAseq to assess whether the MYC signature is being modulated in the BMPC mice and cell lines. Below are the accomplishments for each subtask.