The goal of this project is to develop smart targeted lipid ECO/siRNA nanoparticles (ELNP) to target oncogenic long non-coding RNAs (lncRNAs) as a novel therapy to treat triple-negative breast cancer (TNBC). Metastasis and drug resistance are the main causes for the high mortality rates of women diagnosed with TNBC worldwide. Although targeted therapies have been developed to treat some subtypes of breast cancer, the TNBC subtype is particularly refractory to these therapies. Oncogenic lncRNAs play a critical role in tumorigenesis, metastasis, drug resistance, and immune suppression of cancer by simultaneously manipulating multiple cancer-associated signaling pathways. We have demonstrated in this project that onco-lncRNAs are promising therapeutic targets to treat TNBC, and that downregulation of an onco-lncRNA with systemic delivery of targeted ECO/siRNA nanoparticles results in significant suppression of TNBC proliferation. We have identified a novel lncRNA BORG, which is associated with TNBC development, metastasis, drug resistance and immune invasion, as a compelling therapeutic target to treat TNBC. It is overexpressed in invasive BC, including TNBC, but not in normal tissues. Downregulation of BORG with targeted ECO/siRNA nanoparticles has potential to inhibit metastasis, sensitize TNBC to chemotherapy, and enhance antitumor immunity for curative treatment of TNBC. In this project, we will optimize and develop the smart ECO/siBORG nanoparticles to efficiently deliver siBORG in TNBC to silence the cancer-promoting lncRNA. We will also explore the combination therapy of silencing BORG with a tumor-specific peptide drug conjugate and/or immunotherapy to treat TNBC and to eventually eradicate this deadly disease. The specific aims of this project are 1) to optimize and develop smart siBORG-ELNP for efficient and specific gene silencing in breast cancer cells; 2) to determine the efficacy of targeted siBORG-ELNP as single therapy and in combination with targeted chemotherapy in animal TNBC models; and 3) to determine the efficacy of targeted siBORG-ELNP in modulating TIME for improved immunotherapy in animal TNBC models. Our long-term goal is to develop a novel and feasible therapy based on the smart nanoparticles to treat life-threatening breast cancer.