Estrogen receptor positive (ER+) metastatic breast cancer (MBC) is an incurable condition affecting approximately 168,000 women annually in the US. Fulvestrant, an Estrogen Receptor Degrader, is a standard treatment for ER+ MBC but is limited by dose-related toxicity and the development of drug resistance. To address these issues, we aim to develop a tumortargeted nanoparticle formulation that enhances the efficacy of fulvestrant while reducing side effects. Fulvestrant has been shown to work well as a stand-alone nanoparticle and is predicted to be an ideal candidate as a combinatorial nanocarrier. Combination indocyanine-based nanoparticles (INPs) are a feasible approach to deliver drugs with normally poor pharmacokinetics or poor PD (toxic). INPs encapsulating fulvestrant were created via nanoprecipitation in an aqueous solution and characterized using dynamic light scattering (DLS), transmission electron microscopy (TEM), and high-performance liquid chromatography (HPLC). Drug encapsulation efficiency and nanoparticle stability was monitored over time at various temperatures (4°C, RT, 37°C). Additionally, seventeen rational drug combinations were evaluated for nanometasynergy in co-encapsulated nanoparticle systems, with five combinations demonstrating successful co-assembly, as confirmed by HPLC. This approach aims to leverage the benefits of drug synergy and reduce the likelihood of acquired resistance, as seen in prior studies of meta-synergistic nanomedicines. Among these, we characterized a combinatorial nanoparticle, Fulvestrant-BSJ-03-096 (Nano-Fulv-Pro. We further demonstrated the efficacy of Nano-Fulv and Nano-Fulv-Pro in vitro using MCF7 cells. By combining fulvestrant with rational drug pairs in a targeted nanoparticle system, we report the development of a novel class of targeted nanoparticle estrogen receptor degraders (NERDs).