Small interfering RNAs (siRNAs) are promising for gene-targeted therapies, but their poor cellular delivery limits clinical use. siRNAs face challenges to cross cell membranes due to their anionic charge and large molecular weight, especially in blood cells. To address this, we developed a lipid-conjugated polyethylenimine (PEI) lipopolymer platform designed for siRNA delivery into blood cells. The cationic PEI forms stable complexes with siRNA, while the lipid component aids cellular uptake. These lipopolymer/siRNA complexes, known as lipopolymer nanoparticles (LPNPs), were evaluated in human peripheral blood mononuclear cells (PBMCs), different leukemia cell lines, and patient-derived cells. LPNPs efficiently delivered siRNA in vitro, with a significant extrahepatic in vivo biodistribution profile, particularly to target tissues implicated in leukemia pathology, spleen, and bone marrow. They also silenced oncogenes and induced apoptosis, which leads to reduce the leukemia burden in preclinical models, with minimal toxicity. Importantly, LPNPs did not trigger proinflammatory cytokines in PBMCs from healthy human volunteers, demonstrating both safety and efficacy for leukemia treatment.
Learning Objectives:
Upon attending this session, participants will be able to appreciate how lipid-conjugated cationic polymers are being used to develop lipopolymer/siRNA nanoparticles (LPNPs).
Participants will also be able to appreciate how LPNPs are used to overcome delivery challenges of siRNAs, preferentially targeted to extrahepatic organs.
Participants will gain valuable insights into the therapeutic efficacy and challenges of LPNPs in preclinical models.
