A synergistic tumor-targeted apoptosis reinstatement (STAR) nanoplatform for co-delivering p53 mRNA and venetoclax to restore p53 function and block BCL-2 in TP53-mutated AML

TP53-mutated acute myeloid leukemia (TP53-mut AML) resists venetoclax-based therapy largely due to loss of p53-mediated mitochondrial priming. We developed a Synergistic Tumor-Targeted Apoptosis Reinstatement (STAR) nanoplatform, composed of a cationic liposomal core (STAR core) that co-delivers wild-type p53 (WT p53) mRNA and ABT-199, and a hyaluronic acid (HA) modification for targeted bone marrow homing. The core achieved high encapsulation (>80% ABT-199; >90% mRNA), uniform size, positive zeta potential, favorable serum stability and hemocompatibility, and synchronized rapid release of both agents under acidic pH conditions. In KG-1a and Kasumi-1 cells, the core enhanced cellular uptake and facilitated endosomal/lysosomal escape, exerting potent anti-leukemic activity, as evidenced by dose-dependent cytotoxicity, apoptosis, and S-phase arrest, accompanied by mitochondrial depolarization, ROS elevation, and ultrastructural damage. Mechanistically, the STAR core restored functional p53 protein in KG-1a cells and promoted the proteasome-dependent degradation of mutant p53 in Kasumi-1 cells, along with BCL-2 suppression and PARP1 cleavage. RNA-seq analysis further revealed distinct transcriptional reprogramming in the two cell lines, with KG-1a predominantly enriched in the PI3K-AKT and RAS-MAPK pathways and Kasumi-1 in ubiquitin-mediated proteolysis, the TGF-beta signaling pathway, and the MAPK signaling pathway. Flow cytometric analysis further confirmed that the STAR platform was efficiently and selectively internalized by AML cells, whereas uptake by healthy human PBMCs remained minimal. In leukemic mice, the STAR platform accelerated marrow homing and enhanced co-localization with CD45 + leukemic cells. The STAR core reduced leukemic burden in bone marrow, blood, and spleen, delayed progression, and prolonged survival; the STAR further extended median survival, with an acceptable safety profile at the administered doses. These findings establish STAR as a nanoplatform that restores p53 and amplifies mitochondrial apoptosis to enhance anti-leukemic efficacy in TP53-mut AML, offering translational promise.