Nanoparticle-based drug delivery has been widely used for effective anticancer treatment. However, a key challenge restricting the efficacy of nanotherapeutics is limited tissue penetration within solid tumors. Here, we report a targeted fusogenic liposome (TFL) that can selectively deliver lipophilic cargo to the plasma membranes of tumor cells. TFL is prepared by directly attaching tumor-targeting peptides to the surface of FL instead of the cationic moieties. The lipophilic cargo loaded in the membrane of TFL is transferred to the plasma membranes of tumor cells and subsequently packaged in the extracellular vesicles (EVs) released by the cells. Systemically administered TFL accumulates in the perivascular region of tumors, where the lipophilic cargo is unloaded to the tumor cell membranes and distributed autonomously throughout the tumor tissue via extracellular vesicle-mediated intercellular transfer. When loaded with a lipophilic pro-apoptotic drug, thapsigargin (Tg), TFL significantly inhibits tumor growth in a mouse colorectal cancer model. Furthermore, the combination treatment with TFL (Tg) potentiates the antitumor efficacy of FDA-approved liposomal doxorubicin, whose therapeutic effect is limited to perivascular regions without significant toxicity.