It could work, but the solution has to be both software and hardware, in theory you could make an 040 - or even an 060 run Lisa Office System, but significant portions of the kernel would need a rewrite.
I'd suggest building a new XLerator from scratch rather than adding a hack to a hack. I can disassemble the ISR and we can figure out how to make an 010 or 020 or whatever work. The MMU part will be harder, but it can be done too.
One of the biggest issues I see is that LOS doesn't seem to be 32 bit clean, in my most recent experiments with 1.2.7 I see it use the upper byte in both address registers and even in the PC, but I'm unsure in what way or for what purpose, likely it tags it with something like a PID or segment number or something. I don't know if the userland cares about this, which would mean, rewriting the supervisor/kernel parts would be possible, but otherwise, the machine will be limited to 2^24 or 16MB (which all things considered is a lot more than 2MB it has right now.)
Though, I think at this point, if you're going to go through all that trouble of designing an XLerator and making major OS changes, it may be worth going big and all the way and build a "Lisa 3" around an 040 or 060 or whatever the latest Freescale chip that's still being made, and add color and sound and ethernet, wifi, and USB, etc.