Abstract Hematologic malignancies are genetically heterogeneous cancers marked by a range of chromosomal translocations, among which fusion oncogenes, e.g., KMT2A::AFF1 in acute lymphoblastic leukemia (ALL), KMT2A::MLLT3 in acute myeloid leukemia (AML), and BCR::ABL1 in chronic myeloid leukemia (CML), are particularly aggressive and clinically intractable. These fusion-driven hematologic malignancies are associated with poor prognosis and resistance to conventional therapies, emphasizing the need for fusion targeted, personalized treatment strategies. Small interfering RNAs (siRNAs) offer a promising approach due to their capacity for precise gene silencing. However, clinical translation is hindered by delivery challenges, including rapid degradation, off-target effects, hepatic accumulation, and inefficient uptake by hematopoietic cells, largely due to their negative charge, size, and the limited cytoplasmic volume of blood cells. To address these limitations, we developed a novel lipopolymer-based siRNA delivery platform by conjugating aliphatic lipids onto low-molecular-weight polyethyleneimine (PEI, 1.2 kDa). This modification yielded a series of lipopolymers capable of forming stable nanocomplexes with siRNAs, colloquially known as lipopolymer/siRNA nanoparticles (LPNPs). These LPNPs leverage the cationic nature of PEI for siRNA binding and lipid-mediated mechanisms to enhance cellular uptake. We evaluated the efficacy of LPNPs in delivering siRNAs targeting KMT2A::AFF1, KMT2A::MLLT3, and BCR::ABL1 in preclinical models of ALL, AML, and CML, respectively. LPNP-mediated delivery attained efficient intracellular siRNA uptake and robust gene silencing in all three forms of leukemia cell lines, which resulted significant downregulation of fusion oncogene expression. This silencing induced apoptosis and markedly reduced colony-forming potential in vitro. In vivo biodistribution studies demonstrated enhanced biodistribution of LPNPs in leukemia-accompanying tissues, including bone marrow and spleen, with reduced hepatic sequestration. Particularly, systemic administration of LPNPs led to a substantial reduction in leukemia burden and significantly improved survival in xenograft models of ALL, AML, and CML. Our findings highlight the therapeutic potential of lipopolymer-mediated siRNA delivery for targeting fusion oncogenes in hematologic malignancies. This platform offers a promising strategy for overcoming current delivery barriers and advancing RNA interference-based therapies toward clinical application. Citation Format: Mohammad Nasrullah, Remant KC, Spencer B. Gibson, Xiaoyan Jiang, Olaf Heidenreich, Joseph Brandwein, Hasan Uludag. Lipopolymer-mediated delivery of fusion oncogene-targeting siRNAs attenuates leukemia burden and improves survival in preclinical models of hematologic malignancies abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3018.
Nasrullah et al. (Fri,) studied this question.