A Poly (β‐Amino Esters)‐Based Multicomponent Nanoparticle for Efficient mRNA Delivery to Acute Myeloid Leukemia Cells

Gene delivery to acute myeloid leukemia (AML) cells is crucial for mechanistic studies and targeted therapeutics, yet nonviral transfection methods remain limited by low cellular uptake and inefficient endosomal escape in suspension AML cells. Herein, a rationally designed multicomponent nanoparticle comprising a poly( β ‐amino ester) polymer core for robust nucleic acid complexation, palmitic anhydride to enhance cellular internalization, and the cationic lipid 1,2‐Dioleoyl‐3‐trimethylammonium‐propane to facilitate efficient endosomal escape is presented. Systematic optimization of these components yields nanoparticles with outstanding transfection efficiency (up to 64.4%) and minimal cytotoxicity in suspension AML cells (MOLM13). Utilizing red firefly luciferase‐mRNA as a reporter, rapid and specific enrichment of transfected MOLM13 cells in the pelvic region of mice following intravenous injection is demonstrated. This advanced nanoparticle platform significantly enhances gene delivery to suspension AML cells, promising new avenues for AML research and therapeutic interventions.