Stiffness of HIV-1 Mimicking Polymer Nanoparticles Modulates Ganglioside-Mediated Cellular Uptake and Trafficking

The monosialodihexosylganglioside, GM3, and its binding to CD169 (Siglec-1) have been indicated as key factors in the glycoprotein-independent sequestration of the human immunodeficiency virus-1 (HIV-1) in virus-containing compartments (VCCs) in myeloid cells. Here, lipid-wrapped polymer nanoparticles (NPs) are applied as a virus-mimicking model to characterize the effect of core stiffness on NP uptake and intracellular fate triggered by GM3-CD169 binding in macrophages. GM3-functionalized lipid-wrapped NPs are assembled with poly(lactic-co-glycolic) acid (PLGA) as well as with low and high molecular weight polylactic acid (PLA^lMW and PLA^hMW) cores. The NPs have an average diameter of 146 ± 17 nm and comparable surface properties defined by the self-assembled lipid layer. Due to differences in the glass transition temperature, the Young's modulus (E) differs substantially under physiological conditions between PLGA (E _PLGA = 60 ± 32 MPa), PLA^lMW (E _PLA ^lMW = 86 ± 25 MPa), and PLA^hMW (E _PLA ^hMW = 1.41 ± 0.67 GPa) NPs. Only the stiff GM3-presenting PLA^hMW NPs but not the softer PLGA or PLA^lMW NPs avoid a lysosomal pathway and localize in tetraspanin (CD9)-positive compartments that resemble VCCs. These observations suggest that GM3-CD169-induced sequestration of NPs in nonlysosomal compartments is not entirely determined by ligand-receptor interactions but also depends on core stiffness.