The "mankind are the real monsters" trope comes up a lot in science fiction, and the Foundation provides a really good platform for exploring it. I'm hoping to write up a bit of an inversion of that idea by exploring the Fermi Paradox. Full disclosure: This idea is inspired by another post currently at the top of the "drafts and critiques" forum, so part of this post will be making sure that my idea differs far enough to avoid plagiarism or technically-not-plagiarism-but-still-a-cheap-ripoff.
SCP-NNNN is the planet Earth (or some physical object(s) on/within the Earth), and it is the only planet in the Milky Way with a thriving biosphere. There is some "Great Filter" out there, some entity or natural property of the galaxy that means that intelligent life never lasts long enough to start broadcasting radio waves strong enough for us to detect, and SCP-NNNN protects us from it. A few ways I'm thinking of exploring this
1 — Titanic struggle of Good vs Evil, humanity saves the day: The Great Filter is a malevolent entity/entities that seeks out and destroys life in the Milky Way. SCP-Earth protects us from it with the power of technobabble and/or magic. We figure this out when not only do we never find life in our galaxy, but also every time we try to make an extrasolar colony, it collapses within a few years. The story here is humankind figuring out that they can fight back against the Filter by bringing the right "lucky pebble" along for the ride. Humanity spreads out amongst the stars, sowing the seeds for interstellar civilization and/or contacting life in other galaxies that don't have a Filter.
2 — Humans vs. the Uncaring Void, humanity saves the day: Same deal, except there's no Evil Great Filter Entity, it's just that the odds of life developing anywhere at all are very, very, very, very slim without SCP-Earth catalyzing it. When SCP-Earth touches a planet, it induces abiogenesis (generation of life from non-living matter), and keeps doing it until something sticks and starts to multiply on its own. We figure this one out when we observe primitive alien microbes in the tracks of old Martian rovers — wherever Earth-matter touched Mars, it started trying to kickstart life. In this case, humanity doesn't colonize the galaxy, humanity flies around seeding other planets with their own new, native life, but we can only really live on Earth ourselves. We eventually implode due to climate change or nuclear war or pandemic etc., but our children live on.
3 — Humans vs. Something Nasty, humanity is doomed: I kind of like "hopeful," or at least "bittersweet," better than "doomed." I'd rather avoid this one in general unless I get a really good idea.