Nanoparticles have great potential as drug delivery vehicles or as imaging agents for treatment and diagnosis of various diseases. It is therefore crucial to understand how nanoparticles are taken up by cells, both phagocytic and non-phagocytic. Small interference RNA has previously been used to isolate the effect of particular receptors in nanoparticle uptake by silencing their expression. Here we show that, when it comes to receptors with overlapping function, interpretation of such data has to be done with caution. We followed the uptake of silica nanoparticles by scavenger receptors in A549 lung epithelial cells. While we successfully knocked-down gene expression of several different receptors within the scavenger receptor family (SR-A1, MARCO, SR-BI, LOX-1 and LDLR) this caused reciprocal up and down regulation of the other scavenger receptors. Subsequent nanoparticle uptake experiments in silenced cells exhibit a complex behaviour, which could easily be misinterpreted if reciprocal regulation is not considered. Preliminary identification of the actual scavenger receptors involved can be found by disentangling the effects mathematically. Finally, we show that the effects are still present under more realistic biological conditions, namely at higher serum concentrations.