> Inventory merge / direct access

Sounds like the right direction. Would it make sense to have adjacent/opposing items to automatically map to left/right hand? That way you could set up "kits" in your backpack that you can swap in and out fast.

> - We lost a most intuitive interaction button

I'm not convinced the mouse should be used for interaction. After all, we have to restrict interaction closely around the Clonk (or implement - eww - pathfinding). That seems like the wrong task for the mouse.

And while current items might not use the second mouse button enough, this could well change.

> - Players have to keep track of their current "Hand Setup" (the combination of items)
> - Inventory functionality is more complicated (e.g. swapping hands)

The player is free to just not use one slot, to get the same complexity and utility as with your single-wield solution. That's actually how I imagined this working: Leave the right-hand slot with some background functionality (shield, digging, whatever), and do most work with the left-hand slot.