Effective targeting by uniformly functionalized nanoparticles is limited to cancer cells expressing at least two copies of targeted receptors per nanoparticle's 'footprint' (approx. ≥ 2 × 105 receptor copies per cell); such receptor d. supports the required multivalent interaction between the neighboring receptors and the ligands from a single nanoparticle. To enable selective targeting below this receptor d., ligands on the surface of lipid vesicles were displayed in clusters which were designed to form at the acidic pH of the tumor interstitium. Vesicles with clustered HER2-targeting peptides within such 'sticky patches' (sticky vesicles) were compared to uniformly functionalized vesicles. On 'HER2-neg.' breast cancer cells MDA-MB-231 and MCF7 (expressing 8.3±0.8 x104 and 5.4±0.9 x104 HER2 copies per cell, resp.) only the sticky vesicles exhibited detectable specific targeting (KD ∼ 49-69 nM); dissociation (0.005-0.009 min-1) and endocytosis rates (0.024-0.026 min-1) were independent of HER2 expression for these cells. MDA-MB-231 and MCF7 were killed only by sticky vesicles encapsulating doxorubicin (32-40% viability) or the alpha-particle emitter 225Ac (39-58% viability), and were not affected by uniformly functionalized vesicles (>80% viability). Toxicities on cardiomyocytes and normal breast cells (expressing HER2 at considerably lower but not insignificant levels) were not observed, suggesting the potential of tunable clustered ligand display for selective killing of cancer cells with low receptor densities.