B-cell acute IympnooIast1c IeuKemIa (ALL) accounts for 75% of all ALL diagnoses. Specifically, treating the Philadelphia {Ph) chromosome subgroup (which creates a new gene called BCR-ABL) of B-cell ALL challenging and has high relapse rates and poor survival. Mounting evidence from recent findings suggest that Signal Transducer and Activator of Transcription S {STATS) signaling is a promising therapeutic targE for treating high-risk B-cell ALL. One-way STATS5 signaling can be efficiently targeted is by utilizing STAT5 siRNA, which can precisely knock down the STATS gene and inhibit the proliferation of B-cell ALL cells. C the other hand, a small molecule ligand, NL-1, which interacts with mitochondrial protein, MitoNEET he demonstrated its anti-leukemic activity in B-cell ALL. We hypothesize that a combinatorial treatment strategy that simultaneously targets STATS and MITONEET using STATS siRNA and NL-1, respective! may show enhanced anti-leukemic activity. STATS siRNA is a negatively charged hydrophilic nucleic ac with poor in vivo stability, and NL-1 is insoluble in aqueous solvents. These challenges necessitate significant need to develop a suitable delivery system that can encapsulate and deliver both of these therapeutics precisely to cells. Our preliminary data show that utilizing an ionizable lipid nanoparticle approach not only efficiently encapsulates nucleic acids and small molecules therapeutics but als intracellularly delivers them to B-cell ALL cells in vitro. Two independent aims are proposed to optimize and validate ionizable lipid nanoparticles as an intracellular delivery platform for B-cell ALL treatment. Aim 1: To develop ionizable lipid nanoparticles containing STATS siRNA and NL-1 and optimize their intracellular, release kinetics. Aim 2: Determine if STATS siRNA-NL-1 ionizable lipid nanoparticles will allow du intracellular targeting, leading to enhanced anti-leukemic activity. This application is innovative in multiple ways, including the development of translatable lipid nanoparticle platforms, the dual intracellular delive1 of nucleic acid and small molecule therapeutics, and the testing of ionizable lipid nanoparticle technology B-cell ALL models. To the best of our knowledge, this is the first strategy that utilizes ionizable lip nanoparticles to target B-cell ALL. We expect that once this application is complete, we will have identified the suitable ionizable lipid nanoparticle platform that induces the dual intracellular release of nucleic acid and small molecule therapeutics. Furthermore, we will have determined if combinatorial targeting is optimal, for reducing tumor burden in B-cell ALL.