This is a simple list of suggestions to make the next ME game better than ME 3. Now personally I thought ME 3 was pretty good. It had it's flaws sure, but it didn't engender in me, the nerd rage I've seen online. It's simply my opinion, so feel free to say I'm full of it if you disagree.
1. Scale down the size of the conflict
ME 3's Big Epic End of the Universe plot was so huge, so clunky, that it was literally relegated to the background. I never really felt any significant tension, or ominous empending doom, because all the stuff the Reapers were doing was happening off camera, or was simply an animated background screensaver, while I'm running around the chest high wall map, shooting smaller threats. When your big threat isn't actually part of the story/action, it's not a threat, its backdrop. Make the story about one planet, or one solar system maybe, nothing bigger. Bigger doesn't always mean better. To use a classic example, the first Die Hard movie. Very small scale, isolated environment for the action to take place, minimal list of protagonists/antagonists. Give me an N7 team that's been tasked with saving a city, or planet, or solar system, from a very specific, reasonably sized threat, and I will be a happy camper.
2. Don't mention Shepherd. No, really, don't bring him up. Don't have cameos from the original crew's survivors. The universe is a big freaking place, and while everyone might know about Shepherd's sacrifice, it doesn't mean it's going to come up all the time, with every person. Give me a group of people who have way more urgent things on their plate than talking about what Shepherd did. Just because the game is in the ME'verse, doesn't mean it revolves around Shepherd.
3. Don't do the space travel map stuff. Really did anyone enjoy that stuff? I didn't. It felt like busy work between combat maps, that I was compelled to do in order to get upgraded equipment. Otherwise it was simply a loading screen between chest high wall maps. We have characters who are engineers, scientists, etc, that we spend points into to make them more powerful in these skill sets....let them be the mechanic for upgrading gear. As we put points into their mechanical/scientific skill, it opens up new upgrade options for our weapons/armor and ships. You did something similar in the first ME with the security on the doors, and I liked that, do something similar.
Just a friendly list of suggestions from a fan, that has enjoyed the series, and hopes to see the series being as good, or better in the future.