I have read of elephants being killed with a 22 rimfire throught the ear canal into the brain.
I still would rather have a legal weapon for deer, and that usually starts with 24 cal. (shotguns in IL)
For any defensive firearm, I would want enough power. Most handguns are underpowered, and from hearing first hand accounts by doctors, will not necessarily stop immediately.
I own a couple of 22 handguns, but would not want to use them for defense, if better choices were available. I own a 22 mag carbine, but would rather have a larger caliber for any game larger than a coyote.
22s sure kill the paper targets better than anything else.
For stuff that shoots back, I'd rather have a 357 revolver in a handgun - or a 9mm.
I haven't found a handgun in 45acp that I can shoot as well as a Browning 9 or a Ruger 9, but perhaps I should look at the 40s.
I can't shoot any of the autos as well as a revolver.
The 223 was designed as a military version of the 222. That was a varmint round, and not a deer round. Auto fire is the reason for use of the 223 in the military. It wasn't selected for effectiveness at long range - a 308 is much better for that!
A 24 cal. "short" might be a better choice for a defensive rifle, but I can't see the logic of a 22 cal defensive pistol, if there are better options.