The paradox of gold–liposome nanohybrids: the location of gold governs unconventional properties and drives cellular behavior

The physicochemical characteristics of nanoparticles (NPs) and the cell type they encounter impact cellular interactions. Yet, which parameters should be precisely controlled to direct endocytosis in specific cell types remains paradoxical. Here, we designed gold-liposome nanohybrids (GLNs) and demonstrated for the first time that the location of gold either inside, outside, or partially in/out of the liposomes enables simultaneous tunability of their physical, molecular, mechanical, and optical properties that go beyond the conventional paradigm of size, shape, and charge. Well-controlled chitosan layers on the liposomes allowed the modulation of the position of gold, generating three distinct GLNs of similar size but varied topology (smooth to uneven to textured), surface molecular composition (lipid-rich to inorganic gold), stiffness (4 to 50.5 MPa), tunable resonances (visible to near-infrared) and photothermal conversion efficiency. These collective properties of GLNs governed cellular interactions in two distinct cell types, dendritic cells (DC2.4) and epithelial cells (MODE-K). Our findings show that (i) endocytosis is cell-type dependent and temporally-controlled varying significantly for the three GLNs, (ii) cells show sensitivity to the endocytosis rate even within the narrow stiffness range studied here, and (iii) the properties of GLNs control their therapeutic function from photothermal heating or mild hyperthermia in MODE-K to optically-driven immunostimulation in DC2.4. Our findings may ultimately establish new mechanisms of NP-cell interactions enabling the development of a family of novel NPs with unexplored properties applicable for a range of biomedical applications.