I'd love to see something different for the next Mass Effect title. First off I think a sequel would be best cause we already know what happens before the reapers and Shepard. The only thing you guys haven't done is the First Contact war and that backstory fighting Shepard had to go through before ME1, again we already know how both of those turn out. So for a sequel you guys could jump ahead a good amount of time into the future. If you really want to appeal to fans, you could put Shepard in as a cameo as an old person or aged at least (You could use our old face codes) but it doesn't have to be us meeting them either just for us to know what happened to them if they lived and what about their love interest (Maybe in a readable document thing or it's mentioned by a character).
On the other hand you could skip ahead a few centuries, that would let you make all new characters and if it isn't too far ahead let us see some of the long-lived characters again. Liara and Wrex if they survive would be two possible characters to live a few centuries and see how they're doing.
I was thinking for the main protagonist(s) you could make a character creator for multiple species. For instance something possibly similar to Dragon Age: Origins, in that you guys had the usual human and various backgrounds associated with them, which if you have multiple races would make it diverse if you had at least 3 or so different backgrounds kinda like the spacer, earthborn, and colonist style. Then you had the elves/ dwarves, from what I understand in DAO the story was slightly effected in dialogue when some NPC's would say hello human or hello elf. So in a Mass Effect style you could do a character creator where you can customize the face/skin tone/hair like in previous ME's maybe even body size so maybe you want a bulky or scrawny looking character. I'm also not saying just human, it'd be cool if we could have that type of customization for other races like Asari, Turian, Salarian characters (One aspect I loved in Skyrim and Dragon Age). I'd definitely love to play as at least all the council races but the best thing would be all the various humanoid/ bipedal races like all the council races plus Batarians, Krogan, Quarians ect. Although I'm not really sure how ALL of the races would work out, the Elcor I seriously doubt could work and the Hanar might be hard too (Although Blasto probably is the exception).
Although if you guys did end up doing that that would be the easiest way to include all of the unseen gender variations of the races. I know you guys just recently introduced female Turians but we've only heard about female Batarians and I don't think the unmasked version of a male quarian was ever shown either. So both genders of the customizable races right off the bat would be nice and would get rid of a lot of plot holes.
In the story though, in the romance department. I think if we have a team of characters or at least a group of main characters all of them should be able to become Love interests. New species and old ones would be cool for that. You guys should just make them all bi though cause I know more people would love that unless the character has some problems. I mean it would be past 2186 so you'd think it'd be fine. Regardless more diversity would be cool since if you did go with my idea of multiple races to choose from and both genders for those races, to make it believable you might have to put two different genders of the same species for a squad member.
You could let us pick and choose who we want so let's say you had to pick either a female salarian or a male vocha or maybe even geth since they can live sort of (hint* we've never seen the Raloi either). Anyways both have two different kinds of personalities, we get to choose the squad mates we want with us. I think that would be a cool choice based thing. You could even have the squad members betray the protagonist depending on their decisions and it might be interesting to see subtlety with characters that can be romanced. So you can't tell so easily who can be a LI (Of course that won't stop me from still looking it up on wiki).
So sequel set a bit after ME3, cameo or at least tell us about Shepard, multiple races/genders to customize as the protagonist, choice in squad and let them all be love interests. That's about all my ideas on what'd be cool. I'll leave the general story to you guys cause you usually got that department squared away. Thanks for asking for our opinions but go with what you feel we'd all like the most cause you usually can't please us all. Oh and I miss the Mako 