Nuclear throne runs at 320x240, i.e. 20x15 of 16x16 tiles, and it looks amazing, but that's 4:3 (but not a one-room game).
16:9's bit more of a problem, but take a look at ScourgeBringer (one room per screen game). They use 480x270 (fullhd/4) render texture but grid is 480x272 and they just crop one pixel from the top and one from the bottom - it doesn't matter because first and last rows are always just flat dark background.