Obviously, opponents now have films on Kaepernick and the Pistol offense, so it stands to reason that some teams may be better equipped to face it.
But who says the Niners will be operating exclusively out of the type of offense?
I think we all were pleasantly surprised by Kaepernicks pocket presence and accuracy last year, so relying on a more traditional offense this year (if need be) isn't an issue. But the beauty of the Pistol is the flexibility it provides. Even on plays that are not read options, defenses will still have to respect the possibility of a straight up handoff or Kaepernick breaking the pocket. And inevitably, at some point late in games when fatigue is a factor for the defense, the Pistol will result in some big plays.
The wildcard moreso is the WRs (naturally), but you don't need All Pros out wide to move the football. I liken the Niners offense to the early 2000 Chiefs: strong running game with Priest Holmes and Larry Johnson, top tier TE in Gonzalez and so-so WRs in Eddie Kennison and...? But Kaepernick is the difference maker and if can stay healthy and build upon last year, the offense will remain a matchup problem for defenses.