Hmm... One of the first I would think of is https://mangadex.org/title/46852/11me . Just the title should give you an idea of what the series is about.
https://mangadex.org/title/41161/gorae-byul-the-gyeongseong-mermaid is another one. It's so poignant and beautiful that I get so... idk how to say this. Anyways, it uses some nice symbolism with the little mermaid's story to give it more depth.
This too https://mangadex.org/title/20993/sekai-de-ichiban-ore-ga has a cool concept, and it keeps it more grounded with how it deals with its characters.
Speaking of grounded, there's something regarded as the "better Rent-a-Girlfriend", https://mangadex.org/title/46508/asu-watashi-wa-dare-ka-no-kanojo , though I haven't read the former so this felt really unique to me.
Read this really funny twist on the otome-ge isekai genre https://mangadex.org/title/41333/isekai-tensei-ore-ga-otome-ge-de-kyuuseishu if you're looking for something unique in the isekai field.
And tbh, I CAN'T not spam in https://mangadex.org/title/151/bokura-no-kiseki when we're talking about uniqueness. Well-done characters, worldbuilding, lore, mystery, and relationships, in a package of a manga that predates the popularization of the reincarnation theme? Pick it up.
Obligatory mention to https://mangadex.org/title/15366/magi-no-okurimono for breaking my heart and picking it back up. Heartwarming (?) stuff about death and life.
This https://mangadex.org/title/2966/kimi-wa-petto screams so much character right from the start, that I can't NOT get hooked, and I'm not even done with this one.
https://mangadex.org/title/9589/kasane combines many elements I like into this little beautiful series and supplements them with likeable characters. A keeper.
Now https://mangadex.org/title/8119/wagatsuma-san-wa-ore-no-yome is wacky and weird for a harem/romance.
https://mangadex.org/title/17786/shounen-shoujo is weird too, for sure. Not just in content, but the artist did some pretty experimental things with the art in the manga.
https://mangadex.org/title/1057/pandora-hearts is so memorable, not only to me but to many others too I'm sure, and I haven't managed to find something similar to it so I guess that means it's original?
In terms of bodyswaps, https://mangadex.org/title/10848/shishunki-bitter-change stands out. Why? Cuz the bodyswap is (maybe a spoiler?)
.
This is getting long, so will be back later to post some more stuff.