Very good line of thought - to help crystallize the point, base sets (2 WR with 2 TE and a RB or 2 WR with 2 RB and a TE) are much more efficient for passenger than 3 WR sets. Interesting enough, 4 WR sets are about as efficient as base sets - again, much more efficient than 3 WR sets. When I think about the why, it's pretty clear to me that 3 WR sets are easier to defend (talking passing game exclusively), because most teams now have 3 CB's who can cover at a starting level. For the average offense, you're not going to create mismatches, because your 3rd WR is not going to be significantly better than the opposing team's 3rd CB. Base sets remove the 3rd CB and replace them with a LB, who will not be as good in coverage - especially since teams invest less in LB3 than CB3. Most teams, though, don't have 4 CB's who can cover at a starter level, so if you have 4 WR's who can play, you can create mismatches that way, too.
4 WR sets are kind of the gold standard, because they're also the most efficient personnel package to run out of. Base sets, though, are great for play action, and this is one area where 3 WR sets do well (Rams are the best example), too. Play action passes are much more efficient than straight dropbacks, and play action from Under Center is more efficient than play action from Shotgun. This is where 12 and 21 (base sets) really shines in its ability to put the D in a bind. Eventually, I think teams will shift their defensive approach and counter base sets with more DB's anyway, and then running out of base sets will become more efficient, but we're not there yet. Small sample size, but play action out of Pistol is even more efficient than play action Under Center, and I think teams should implement more Pistol concepts (always thought it was underutilized, but it's nice to have some evidence to back up those suspicions).
These are all broad, big-picture points, and the effectiveness of each package will vary depending upon the opposing D, so I think it's best to adopt an approach of adaptability, where you can take advantage of the weaknesses of a given opponent. NE does this better than anyone. In building a team, though, I'd want plan to run the majority of my plays from base or 4 WR sets, with some 3 WR or extra heavy (1 WR) sets peppered in.