A particularly fun, if not very difficult, one is the "All Wizards" party. With the interesting thing being that you can still get a fairly diverse party thanks to Abjuration Tank and MDPS Spellblade builds (You can even have the remaining 2 Wizards split between Summoner/Support and offensive caster). It's a little trickier if you go PURE Wizard rather than allowing multiclass dips (1 level as Fighter on Abjuration Tank for Heavy Armour proficiency, 2 levels as Sorcerer on Summoner for Twinned Haste)
A more challenging run would be to use ONLY enemies as weapons. Meaning throwing and improvised weapon attacks using enemies. You can make it more tricky by banning use of Strength Elixirs meaning that you have to hit 20+ Strength naturally to be able to deal with human-sized enemies (Which means trying to get to Grymforge ASAP for the masks).
Barrels only. While yes, they're OP for cheesing singular encounters. Having to sort out inventory management after the nerfs and manage them tactically to get through all encounters in the game would offer some challenge.
