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Stealth liposomes, obtained by surface decoration with hydrophilic polyethylene glycol (PEG) molecules, represent an important turning point in liposome technology, leading to significant improvements in the pharmacokinetic profile compared to naked liposomes. Nevertheless, the generation of effective targeted liposomes\u2014a central issue for cancer therapy\u2014has faced several difficulties and clinical phase failures. Active targeting remains a challenge for liposomes. In this direction, a new Super Stealth Immunoliposomes (SSIL2) composed of a PEG\u2010bi\u2010phospholipids derivative is designed that stabilizes the polymer shielding over the liposomes. Furthermore, its counterpart, conjugated to the fragment antigen\u2010binding of trastuzumab (Fab\u2019<jats:sub>TRZ<\/jats:sub>\u2010PEG\u2010bi\u2010phospholipids), is firmly anchored on the liposomes surface and correctly orients outward the targeting moiety. Throughout this study, the performances of SSIL2 are evaluated and compared to classic stealth liposomes and stealth immunoliposomes in vitro in a panel of cell lines and in vivo studies in zebrafish larvae and rodent models. 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