The root of the bolt handle could no doubt be fitted to act as a locking lug. An additional thought on using an existing .22 bolthead - it would probably work better if that part of the bolt didn't rotate. Think about how most .22 bolt rifles are set up, with a non-rotating head, and a rotating rear with the locking mechanism. Bolthead would need a guidelug to run in the left boltway.
If it were desired to use an offset bore, to allow the centrefire firing pin to strike the rim, it would be easy enough from a machining point of view to centredrill the barrel blank offset before turning the barrel on centres. This would produce the desired offset. The bore would be angled in the blank, and this would create its own issues.
If the barrel face is in the same position as the .303 barrel face, the rifle would be very difficult to load, unless the receiver ring were dramatically cut away.
Fortunately, no mention has been made of a repeating action, which is just as well.
The three designs that would be worth studying are the M-2 Springfield, the Israeli Mauser conversion, and the Remington 40X .22. All three use a receiver originally made, or proportionnned, for centrefire.
I suppose such a conversion could be done, if enough time and effort were committed. At a reasonable hourly rate, though, the cost would be substantial. A second one would be a lot less expensive, once a workable system was developed.