Getting a widebody to within a couple of percent of a narrowbody of same cabin floor area is possible. But the physics can't be avoided.
First, weight matters. So it's virtually impossible to build a tube and wing with the same engines and MTOW with a significant increase in fuel economy without a significant diet. 1a is that the for a certain payload the fuselage must support the structure. So if the designers did a good job with the A330 or 787, there's not much weight savings to find in the fuselage. Add in newbiepilot's observation that fuselage is 15% or so of total weight, and it would appear that there is not much gain to be had in totally redoing the fuselage. Lighter skin panels might be worth it, but that's about it.
Second, fuel consumption is not just fuel efficiency. It's fuel efficiency times thrust. If the Trent XWB is 10% SFC better than the Pratt GTF (not saying that's the case, just making an example), but has twice the thrust, the Pratt GTF will burn about 40% less fuel on an absolute basis. Not to mention the weight difference.
So the key is to make a GTF or LEAP work in the application.
Early 767-300s and A300s had engines with less than 50000 lb thrust, and were transatlantic in range. So the base airplane should be doable in 767-300 to A300 size. With regards to the 767, there were airport constraints (LGA with 7000 ft runways and gate size limits) that compromised even a 1970s wing. Wingspan has grown since then and airports accommodate A330 wingspans easily. Also, Airbus A330 CEO needs over 9000 feet takeoff distance when fully loaded, and that is alright with airlines today.
So first is big wingspan. And since Cd is a direct factor of aspect ratio (everything else being equal, 10% higher aspect ratio gives 10% lower Cd (
https://www.grc.nasa.gov/WWW/K-12/airplane/induced.html ). The A330 has 197 foot wingspan vs 767-300 156 ft, or 26% greater wingspan. Which gives about 25% better aspect ratio - and 25% better Cd - right there.
So the MOM should have as long of a wing as they can get away with.
Next is wing area. For a given wing length, less area increases the aspect ratio. So the designers should shrink the wing, and particularly the root chord, as much as they can.
Then there is fuel. An A321 starts with about 7000 gal. Leeham says eachi ACT adds 2.4t (about 800 gal) fuel. So 3 ACT gives 9400 gal Leeham also says the A321neoLR can fly 52t 4000nm with this configuration (if eacih passenger with bags weighs 220 lb, 200 passengers and bags is 44000 lb or 20t. The fuel weighs 28.2t, so that leaves 4t or so for cabin equipment and catering. No cargo. Bags are bulk loaded. It's questionable, and Leeham alludes to that, but I will leave it as is.
Prorated, 220 pax should be at about 31t (10185 gal) and 250 pax should be at about 35.25t (11574 gal). The 767-300A carried 16000 gal and the A300-600 18000 gal. Each would need to get by on about 6000 gal less to be equal to the A321neoLR.
The 767 wing box fuel tank holds 8000 gallons. The A330 wing box fuel tank holds 12000 gallons. So to increase aspect ratio, the wing box becomes the primary fuel storage. It should be enough for the A330 if the other requirements can be met, while the 767-300 would need 3000 gallons (vs 16000 currently) in the wings. So the last spar could be removed and the wing area reduced by 20%. For the A330 that's a 12% reduction in drag. For the A300 (with the A330 wing box) the L/D improvement might be 30% or more. Which suggests 43000 lb thrust (down from 48000 for GE CF6-80A on 767-300). So a new wing could reduce thrust enough for this to work.
What about weight? The A321neoLR is 97t. Proportionally, the 220 pax (767-300) would need to be 107t, and the 250 pax A330 would need to be 121.25t. The 767-300A is 159t, and the A300-600 is 172t. So the 767 would need to lose about 42t, and the A300-600 about 51t. But there's another way to look at it. The OEW of the A321ceo is 48.5t. Add 4t for the heavier neo engines and 2t for the 3 ACTs and hardware, and the A321neoLR should be about 54.5t. (Leeham says the A321neoLR needs an OEW of 52t to work, but without weight savings elsewhere, that won't happen - probably MTOW will end up being 100t, but that's just my opinion). Proportionally, the 767 needs 61t OEW, and the A300-600 needs 68.2t The 767 is 82t and the A300 is 89t. Each needs to lose 21t. Engines go from 9200 lb to 6000 lb (GTF) each, a reduction of about 3t. About 2t can be taken out of structure due to less weight and less thrust. If the wings are 40% of the weight, and they are reduced by 25% of area, that's a 10% weight savings, 8.2t in the 767 and 9t in the A300. So the 767 is 13t lighter and the A300 is 14t lighter. Still have to find about 6 to 7 tonnes. But that 6 to 7 tonnes equates to a 3% to 3.5% fuel economy miss. And the payload margins have not been changed. These hypothetical aircraft may be able to fly their original payloads of 55t for the 767 and 50t for the A300. Versus 42t for the A321neoLR. So if we assume the A321neoLR payload is sufficient, these hypothetical aircraft should be able to fly the A321neoLR payload farther, or fly more payload the same distance.
Maybe the widebody MOM aircraft isn't so farfetched after all.