In addition to potential reductions in on-target efficiency, chemically modifying siRNAs will not necessarily eliminate seed-based off-target effects.
Rasmussen et al. found that a chemically-modified siRNA can still have substantial seed effects.
They examined the expression data for 3 siRNAs from Jackson et al. and showed that for one of them the seed is still active following chemical modification.
The algorithm of Rasmussen et al. (cWords) looks through a ranked list of 3′ UTR sequences (in this case, ranked by deregulation as measured on a microarray) and finds words that are enriched towards the top of the list.
The seed target sequence of the unmodified Pik3ca siRNA is strongly enriched (B panel), as expected, but is also strongly enriched after chemical modification (C panel):
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