I think what defines RE4 best is that it's the first game in the series to get enough love and attention to really make it shine, which you can see from the clear design and inspiration that permeates through it. When I say that, I mean it has a consistent theme, that theme being to recreate a cheesy horror action film in videogame form, literally nothing else. It's the simplicity in design that's responsible for making average things into great things.
What I've always wanted was an Animatrix-style spinoff of the drawings shown in the ending credits, the ones that show the Ganados while they were still peaceful villagers, but get slowly corrupted and overtaken by the Los Illuminados and you can see as everything shifts from being nice and almost playful, to extremely dark and violent as the community becomes infected. That would have been so badass IMO, and I'm honestly surprised it was never capitalized on.
While I don't think RE5 had clear direction or inspiration like RE4 had, I still think it was an improvement on the mechanics. Namely, the melee system, which is the one thing that kept me enthralled in the game for far longer than I should have, just because of how satisfying melees were.
Going into a tangent here: I didn't like how the Majinis were uninspired compared to the Ganados. Going into the little information repository of the game, you found out that the Majinis had uninteresting names like "Machine gun majini" or "Chainsaw Majini" or even "Tribal Majini" and that really pissed me off when the Ganados had names that actually gave them character and a little personality like "Dr. Salvador", "J.J.", and "Miguel".
Alot of people didn't like Sheva, and I can understand that (Me flashbacking to my moments of "GODDAMMIT SHEVA!" such that it became a meme between my friends, and we'd blame Sheva for our failures in unrelated games) but I still think she's an interesting enough character to make appearances in future RE games, but I say that like I say that I think Ashley should be in future RE games, except more mature and having learned combat and weaponry. It's just a consistency between games that I would personally enjoy rather than each game being it's own internalized monster circus.