To confirm the in vitro findings regarding the preferential uptake of IL-13-LCL-SIM by M2 macrophages and the efficiency of the sequential therapy consisting of IL-13-LCL-SIM and PEG-EV-DOX in in vivo settings, syngeneic C57Bl/6 melanoma-bearing mice (n = 5/experimental group) were injected i.v. with 5 mg/kg SIM in free form or encapsulated in liposomes conjugated on days 7 and 10 after tumor inoculation and with 2 mg/kg DOX, free or incorporated in PEG-coated EVs on days 8 and 11 after tumor inoculation. The gene discussed is IL13; the disease is melanoma.