Biodistribution experiments in naive tumor-free mice confirmed that CpG-Stat3 siRNA is specifically internalized by resident macrophages in different tissues as well as DCs and B cells in lymph nodes ( Supplementary Fig. 7) . We also assessed the uptake of the CpG-Stat3 siRNA by macrophages and DCs in tumor-bearing mice. C57BL/6 mice with B16 tumors were injected peritumorally with CpG-Stat3 siRNA (FITC) at 0.78 nmol (20 μg)/injection. Immunofluorescent staining showed myeloid cells positive for CpG-Stat3 siRNA accumulated at the injection site (Fig. 3a) . Flow cytometry also indicated the presence of CpG-Stat3 siRNA in tumor-associated myeloid cells ( Supplementary Fig. 8a ). Furthermore, in vivo intravital two-photon microscopy showed the presence of FITC-positive cells in tumor draining lymph node (TDLN), as early as 1 h after injection of the labeled construct ( Fig. 3b, Supplementary Fig. 8b and Supplementary Fig. 9 ), but not in the contralateral lymph nodes (Supplementary Fig. 9 ). Additionally, high resolution imaging by intravital two-photon microscopy revealed an increased number of FITC-positive cells in TDLNs, as well as an accumulation of FITC-labeled CpG-Stat3 siRNAs in perinuclear endocytic vesicles (Fig. 3b, bottom right) , which was also observed in cultured DCs (Fig. 2c) .