Project Summary Among all racial groups, African American men have the highest rate of prostate cancer, and their cancers exhibit a more aggressive biology, leading to higher rates of death. Although systemic treatments have been developed for this disease, these are primarily palliative; additional treatment strategies need to be developed. The major objective of this proposed project is to develop new targeted therapeutics to improve treatment of patients with advanced prostate cancer, including African American patients who have a particularly worse prognosis and whose tumors harbor more of an inflammatory and immune signature. CD24, a cell-surface glycoprotein, is not expressed in normal prostate epithelial cells but is expressed in approximately 50% of prostate cancers and in 60-66% of African American prostate cancers. For humans and mice, CD24 expression is associated with prostate cancer metastasis, and for patients with prostate cancer, over-expression of CD24 is associated with tumor metastasis and poor prognosis. Notably, a CD24-p53 axis contributes to African American prostate cancer disparities. In addition, CD24 is the dominant innate immune checkpoint in human cancers and is a promising target for cancer immunotherapy. Thus, CD24 may have dual functions as a cell-intrinsic oncogene and an immune suppressor, and it is a potential therapeutic target for patients with metastatic, castration-resistant prostate cancers. We hypothesize that targeting the CD24-p53 axis is an effective therapy for African Americans with metastatic castration-resistant prostate cancer. In this application, we propose a) to synthesize and characterize multifunctional nanoparticles for targeted delivery of anti-CD24 antibody and PRIMA1 (a p53 inducer), b) to evaluate targeted delivery of CD24/p53 targeted multimodal therapy to reduce prostate cancer racial disparities, and c) to determine the molecular mechanisms of the targeted therapy. Our proposed work is expected to establish CD24 as a new therapeutic target and to demonstrate a new therapy that meets the needs of African American patients with metastatic castration-resistant prostate cancer.