My dad always said to stay out of these kind of arguments and he was usually right about most things. In spite of that, here goes. If you need an ultra-small self defense gun, then the .25 ACP is a far better choice than the 22 LR. First of all the .25 is more powerful. I've personally chronographed them from equivalent beretta's. A 40 grain .22 LR runs about 750 to 780 ft/sec. The .25 ACP gives an honest 850 ft/sec, which can be easily duplicated by the handloader. And... if you're a bit venturesome, you can handload the .25 ACP up to 900 ft/sec and maybe a bit beyond with a slow burning "magnum" powder and compressed loads. (For the expansion ratio of a .25 ACP, unique is the equivalent of a "magnum" powder.) Additionally, a 50 grain bullet is 25% heavier than a 40 grain long rifle, and the .251 bullet is 13% larger in diameter than the .222 diameter long rifle. The sectional density of the two bullets are about the same, and so I would expect similar penetration. In summary, the .25 ACP is faster, larger in diameter, and heavier.
Secondly, and most importantly, the .25 ACP is more reliable. My beretta 21 has never mal-functioned from the first round, the first time out of its box. I've never found a reliable .22 mini pocket pistol, and that includes beretta's and high end walther TPH's. Certainly .25 ACP ammuntion is more costly than .22 lr, but for a self defense application, ammunition expense becomes less important than functional reliability and your life.
Thirdly, as for expense, I thought that was why God made dies and reloading presses. You can reload .25 ACP for the cost a a small pistol primer and the bullet. At 1.3 grains a charge, powder cost is pretty insignificant and you can usually find all the brass you want at shooting ranges or shooting areas. (The only difficulty is distinguishing it from .22 lr. You have to get pretty close to the ground!)