That is a big one, inter process messaging securely.
The other one is memory deduplication. Uncontainerized libraries get code stored in memory once. When two applications use the same library, only library variables are duplicated, executable code is stored once.
When two flatpacks package the same library, they duplicate memory use. This is has to be addressed if we're thinking of replacing regular packages altogether.
Ok, suppose we got over that technical jump and can share code memory among different flatpacks. What happens when one of them is updated and packs a newer version of the library? Can we use the newer version for both? Are we breaking compartmentalization by doing so? Or by the very sharing of it?
The concepts need to be worked out (a big hurdle), then implemented. At this point, are we departing too much for the concept that we're essentially creating just another package format?
I don't have these answers, but I think there's a good chance the answer to those will limit flatpack (and competitors) application as the end-all, be-all package format.