It's pretty near perfect...
I cannot, for the life of me, figure out why this isn't more popular...
The graphic style is now very refined, in keeping with an emerging standard in flash-games. The transitions between the different stages is nicely done.
Upgrade system feels pretty balanced, I like how it's more effective to use an array of weapons than everyone using the same one. The specials are a nice touch as well, although one that speeds up the sisters and max scrolling speed, would've been nice.
Soundtrack is more adventurous and, dare I say, mainstream (for flash games, anyway). I personally preferred the more whimsical sound of the previous installments, but that's solely a matter of personal preference. Overall, it's a very good soundtrack. Kudo's to Comp112.
The overall gameplay is a little on the easy side. There were very few times where I felt under-challenged, even late in the game. Even so, the game commanded a high level of concentration, and I actually wasn't able to follow the story this time, even on a second playthrough.
Bosses definitely needed to be made harder.
The pacing of the entire game might need a minor tweak, perhaps sped up to around 130 or 150%. Goes for the obstacles as well as projectiles, and our leading ladies of course. The reload times could stand to be twice as fast. Overall, I think those minor changes in speed would make the game much more exhilarating, chaotic, and fun. I actually only really noticed the lack of speed on my second playthrough, when I was going for a faster time, but if there's one area where this submission could definitely stand to improve, it'd be pacing.
That gripe aside, this is definitely the finest side-scroller I've ever encountered.