Game Genie would be easier. Game Genie monitors the access of ROM and patches values (which would be needed to crack region protection) so you could easily develop cheat codes on the same principal, afterall that's what Game Genie does. Now you are right about GameShark, that is a different cheat system more like Pro Action Replay. Those devices steal an interrupt, probably NMI, to rewrite RAM values every frame. This is more likely to cause problems than ROM patch codes like Game Genie.
The connector apparently you can use one of these 32bit PCI card connectors was it? You just physically modify it a bit and you're good to go apparently.
So again, Game Genie type ROM patching should be doable. Game Genie works usually by a simple encoded string that contains the address to intercept and the value to replace with. On NES and Gameboy they also have "Compare" values due to bankswitching. I don't think that is needed for PC-Engine since the cartridge connector has all the address lines for an 8 megabit ROM, so only SF2CE would be left out.
It seems doable to me, you just need a boot rom/bios to enter patch codes which will in turn configure registers on a CPLD for what addresses it should be looking to intercept and respond to. I mean basically we are just talking about making a game genie for PC-Engine/Turbografx 16 which could easily have been done back in the 90s if they wanted, plus adding a region pin swapping.