I love sci-fi, that's the only theme I ever do. I think the key to make a sci-fi setting is to take the present day and exagerate any issue or development to a certain point, make everything almost possible and absurd enough to be just barely believeable but still far from being complete fantasy.

I also think it's a good idea to take old cliches and reinterpret them in a different way.

I think it's better to take science fiction and fantasy as setting ideas than as a genre you have to kind of be inside. When I am thinking about world-building (not very frequently these days) I mostly think about the kinds of aesthetics that best fit with what I want to discuss in the game. Often with me it comes out kind of sci-fi but that's a reflection over the kinds of thoughts I have ("What would it be like to graffiti a space station?", "Suppose there were gods like those of greek mythology active in the 1920s.") rather than a conscious choice to think up a "Science Fiction" universe or plot-line. Maybe you are really into using genres to plan settings, but don't you think it can get in the way of what you really want to explore?

Yes, I am suggesting that the reason there are so many science fiction clichés is that people take the bounds of the genre too seriously. I mean obviously it is still important to be aware of the genre if you're prone to science oriented settings but it might be useful to think less about sci-fi and more about everything else.

What bothers me is that a lot of people are talking about "doing research."  Science Fiction was originally about basically having strange science without much explanation.  One of the first Science Fiction authors (Short Stories from the late 1800's) actually wrote about a dog.  It was about a kid who kept wondering why his parents protected all the spare "rations" into a giant metal container.  There were several hints along the way that the "parents" weren't the same as the "kid."  At the end, it switches perspectives to the parents who pet "rover" on the head, while taking the garbage out to a compost heap.

A good Science Fiction (or even writer) is usually well-read themselves.  Personally, if you're looking for ideas, a good thing to do would be to hit up a sci-fi blog (I enjoy io9.com) and read the summaries/news of the latest short stories, novels, movies, etc.  And a good sci-fi writer doesn't need to explain everything.  It's easy to use a "black box" design on some things.  Why are the characters in space?  Because the era is set in space.  Because the characters are curious teenagers and went in.  Because the characters are abducted.  Sometimes, it's best to keep things as simple as possible and focus on the truly important themes and messages or stories that you wish to tell.  If your characters all fight in space with swords in the future (a cliche a lot of people hate) maybe its because guns are outlawed.  Maybe they have magnetic shields that repel high-velocity metal?  Maybe their culture defines guns as cowardly or ineffective?  Maybe because everyone's in a dense atmosphere (similar to water) where bullets won't do much of anything?  It is a cliche, but unless you  decide to invent a new type of weapon class, then you'll always have traditional melee/ranged weapons, albeit with changes.  Think of the practicality and the scenario.  There are plausible reasons and thoughts.

Popular thoughts (in the past, at least) were always to consider up-and-coming technologies and then zoom into a time where this is common.  Nanotechnology is very limited and new right now.  In another 60 years, how does it alter daily life?  In the 40's and 50's, Arthur C. Clarke started to write a short story called "The Sentinel" that then went on to be expanded into 2001: A Space Odyssey.  When you think about it, the 60's were the space race.  He wanted to go into depth of these themes and used up-and-coming thoughts.  Our plagues and illnesses and the unknown have greatly influenced the release of zombie films, games, and comics.

Just a few things for consideration.

In a situation like this, the one question you should think long and hard about above all else is exactly why do you like Science Fiction settings so much in the first place?

You can use your answer(s) for that question to inspire or develop your setting or story. If the reasons you give yourself are honest and truly your own, then you should be able to generate some truly unique concepts based on how much creativity you apply to those thoughts.

think about somthing that wouldn't norrmaly be associated with sci-fi and then try to intergrate it (reasonably) to try and remove some cliche like for example, small nano bots constantly swarm the player awaiting for commands, when given they bots carry out the commands to give an effect, the commands are words and effects can range from simply swarming an enemy to a giant blasmaball generation to lightning arcs (basicly sci-fi magic).
can't really think of any other advice tbh.

do drugs and lay in your bed thinking about how badly humanity can fuck everything up in the future. if you can't think of something using this method you aren't meant to be a science fiction writer.

do drugs and lay in your bed thinking about how badly humanity can fuck everything up in the future. if you can't think of something using this method you aren't meant to be a science fiction writer.

Make sure to incorporate the drug use into the story/setting somehow.

Space drugs are the best.