Is there any particular reason, now that there are no more expansions, patches, etc. to come, why we couldn't make backup copies of core game files and begin editing them directly (not so much for upload and sharing as for our own personal games?)

Obviously it would be tricky and probably inadvisable with highly complex mods, but what would be the downside to putting, say, simple bugfixes, default replacement files and the like directly into the game files (one or a few at a time, of course, with appropriate testing) to save disk space and load time?

Yes, you could, but I don't think it'd do what you're hoping? The improvements in load time would be pretty minute - actual override mods are almost always tiny, since they only need to override specific resources, and most objects and textures require the full set of files in the package in order to run. You'd also need to put a lot of effort in to make sure that you didn't accidentally end up with group/instance conflicts if you put original content in the main game packages, and I don't really think you'd get any benefit from the process.

The obvious downside would be if you downloaded a mod from someone else which had a conflict. It'd be incredibly hard to figure out, because you wouldn't have any easy way of identifying which parts of the code were mods and which were original content.