Baiting-enhanced extravasation of lipid nanoparticles for targeted co-delivery of decitabine and siTNF-α to the bone marrow niche in leukemia therapy.

Acute myeloid leukemia (AML) remains a fatal malignancy with poor prognosis due to limited drug bioavailability and therapeutic resistance within the protective bone marrow niche. Here, we present a bone marrow-targeted lipid nanoparticle employing a "Bait and Extravasation" approach for the co-delivery of a hypoxia/ROS-responsive decitabine prodrug and TNF-α siRNA (BIS-LNPs@DCA-siTNF). BIS-LNPs@DCA-siTNF are engineered with a hypoxia-cleavable CXCR4-mimetic peptide for CXCL12-guided chemotaxis and a CLL-1-targeting ligand for selective leukemia cell uptake and tight junction disruption. Optimized formulations with liposomal-encapsulated bleb-like internal structures exhibited high siRNA loading, colloidal stability, and stimuli-responsive release under hypoxic and ROS-rich conditions, effectively mimicking the AML microenvironment. Mechanistically, TNF-α silencing synergized with decitabine-induced cytotoxicity to disrupt leukemia-adipocyte metabolic crosstalk, impair fatty acid metabolism, and promote apoptosis and cell cycle arrest. In an orthotopic AML model, BIS-LNPs@DCA-siTNF preferentially accumulated in bone marrow, significantly reduced leukemia burden, and reprogrammed the microenvironment to elicit anti-leukemic immunity, leading to enhanced CD8+ T, natural killer (NK), and natural killer T (NKT) cell infiltration in the bone marrow site. Furthermore, BIS-LNPs@DCA-siTNF attenuated osteoclastogenesis, restored bone integrity, and improved locomotor performance. These results establish BIS-LNPs@DCA-siTNF as a programmable nanoplatform that overcomes both pharmacological and microenvironmental barriers, offering a promising approach for enhanced AML therapy.