Objective In our previous studies we demonstrated efficient mitochondrial targeting of nanocarriers by surface modification with triphenylphosphonium (TPP). Our current objective was to develop a dual functionality nanocarrier with transferrin (Tf) for tumor targeting and TPP for mitochondrial targeting. æMethods: Liposomes were prepared by a lipid film hydration technique using different combinations of egg phosphatidylcholine (EPC), cholesterol (Chol), Tf-PEG-PE and TPP-PEG-PE/PEG-PE (8 mole %) in the case of TPP-PEG-PE modified liposomes (TPP-L and Dual-L) or simply PEG-PE modified liposomes (PL). Paclitaxel (PTX) was loaded in liposomes for cytotoxicity analysis. Human cervical carcinoma (HeLa), human ovarian carcinoma (A2780) and normal mouse fibroblasts (NIH3T3) were used for cellular studies. ææResults: FACS showed that TPP-L treated HeLa cells had a 1.6 fold higher cellular association than cells treated with PL. Co-localization experiments on HeLa demonstrated significant cellular internalization and mitochondrial co-localization of TPP-L compared to PL. FACS on NIH3T3 and A2780 showed a cancer cell-specific higher association of Dual-L compared to TPP-L. FACS results were confirmed by fluorescence microscopy, demonstrating cellular internalization of TPP-L was significantly increased upon liposomal surface modification with transferrin. Cytotoxicity analysis demonstrated the lack of interaction of PTX-loaded Dual-L with non-target cells and confirmed efficient delivery of PTX to cancer cells, resulting in greater cytotoxicity of Dual-L compared to TPP-L. æConclusions: TPP-L target mitochondria efficiently. TPP-L with an additional transferrin modification have higher cancer cell-specific cellular interaction, resulting in greater efficacy. Results using this newly developed system support their promise as a potential treatment strategy for cancer.