Our results have shown that IL-13-conjugated liposomes were preferentially taken up by M2 macrophages and the sequential targeted therapy consisting of IL-13-LCL-SIM and PEG-EV-DOX was most effective in inhibiting B16.F10 melanoma growth via strong reduction of TME angiogenic capacity and macrophage infiltration, as well as by inducing an oxidative stress-related increase in tumor apoptotic status. Here, IL13 is linked to neoplasm.