I do not intend to hit the database 50 (100, 200+?) times, actually cross the whole stack, for just one query (that is very common)

Most relays don't take 50 filters or 50 subs at the same time, so you need to split it, resolve some npubs, mark the EOSE, move to the next group and so on. Then use the eose cache for each sub to avoid downloading the same event many times.