Targeting cell-surface receptors with nanoparticles (NPs) is a crucial aspect of nanomedicine. Here, we show that soft, flexible, elongated NPs with poly-ethylene-oxide (PEO) exteriors and poly-butadiene (PBD) interiors - PEO-PBD filomicelles - interact directly with the major high-density lipoprotein (HDL) receptor and SARS-CoV-2 uptake factor, SR-BI. Filomicelles have a ~ 6-fold stronger interaction with reconstituted SR-BI than PEO-PBD spheres. HDL, and the lipid transport inhibitor, BLT-1, both block the uptake of filomicelles by macrophages and Idla7 cells, the latter are constitutively expressing SR-BI (Idla7-SR-BI). Co-injections of HDL and filomicelles into wild-type mice reduced filomicelle signal in the liver and increased filomicelle plasma levels. The same was true with SCARB1(-/-) mice. SR-BI binding is followed by phagocytosis for filomicelle macrophage entry, but only SR-BI is needed for entry into Idla7-SR-BI cells. PEO-PBD spheres did not interact strongly with SR-BI in the above experiments. The results show elongated PEO-based NPs can bind cells via cooperativity among SR-BI receptors on cell surfaces.