There is no reason why an aircraft cannot be larger than the -225 and still be able to fly. If you fulfill 1 of 2 of the following conditions, anything will fly.
a) provide enough vertical thrust to counteract the effect of gravity.
b) provide a large and strong enough wing with sufficient airflow to produce enough lift to counteract the force of gravity.
Granted, we reach a point where fulfilling the above is impractical.
The only reason an aircraft larger than the an-225 would be improbable is that it would be so limited as to where it can and cannot land, that it would be almost impossible to find any practical application for an aircraft of its size.
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