Antileukemic activity of miR-29b reduced the leukemic progression in the hROR1 × TCL1 mouse model. (A) The miR-29b treatment (2A2-miR-29b-ILP, 15.7 ± 4.6 × 1000 cells/μL; n = 8) showed significant therapeutic efficacy as evidenced by decreased circulating leukemic B220⁺CD5⁺ cells by >50% in peripheral blood (2A2-scramble-ILP, 38.4 ± 7.3; n = 6; P = .0184). (B) Evaluation of leukemic burden in peripheral 2-week posttreatment revealed ROR1-targeted delivery via 2A2-ILP effectively limited leukemic cell numbers (122.4 ± 23.2 × 1000 cells/μL; n = 7) compared with nonselective IgG-miR-29b-ILP (237.1 ± 40.0 × 1000 cells/μL; n = 6; P = .022). (C) Reduced splenomegaly in hROR1 × TCL1 mice by 2 weeks posttreatment with 2A2-miR-29b-ILP compared with the 2A2-scramble-ILP control (P = .0002; n = 4). (D) Immunoblot analysis of splenocytes from treated mice revealed downregulation of miR-29b targets such as DNMT1, DNMT3A, and SP1 at protein level after 2 weeks of in vivo treatment. (E) Significant reduction in GDM in mouse splenocytes 2 weeks posttreatment with 2A2-miR-29b-ILP compared with 2A2-scramble-ILP control (P < .0001; n = 4).