U2 will have a mainstream radio hit again if they don't try for one and just put out their best material without regard or thought to whether or not it will get played on the radio.
For those of you with failing memories or are too young to remember, With or Without You was like absolutely nothing else being played on radio or MTV (yes, MTV was once a real force and actually used to ONLY play music) at the time. And yet once released got massive play on each.
The problem with this is the age bias present on popular radio today. When is the last time you heard an artist over 50 have a big hit on mainstream radio? It has NOTHING to do with the music and everything to do with the age of the band. Artists like Foster the People, Florence + The Machine, GOYTE etc. have all proven that music that is "different" can still get played a lot. What differentiates those artists from U2 (besides U2's obvious legacy as one of the best bands ever and not merely the flavor of the month) is age. They're all in their 20s or 30s.
U2, unfortunately, are not. They've been in the business for over 30 years and they're 50+. Most people consider them to be an old band. Most radio stations won't even consider giving them airplay, regardless of how good the music is because they're old. Other artists like the Chili Peppers, Pearl Jam, Springsteen and the Stones (when they release new music) have faced the same issue. The difference is, they've adjusted to it and continue to make music that is fulfilling to them. They don't care as much about commercial success. They're not worried about being "relevant". U2 (or at least Bono) have yet to accept this. If they did, they'd see it's more important to build on their legacy by releasing good music regardless of its radio-friendliness.
Honestly, I don't understand why Bono is so hung up on this--perhaps it's ego or being attention hungry? Even without U2 getting tons of attention on the radio, he's still Bono and he's still "relevant." You still hear about him all the time because of his charity efforts. You still hear about U2 because of the massive success of 360. So if it's an issue of ego, Bono is still getting his ego stroked plenty.
I just wish someone would shake some sense into Bono and possibly the rest of U2. They need to realize that the radio hit days are over and that it's better to just focus on the quality of the music, rather than continually scrapping things because it's not "radio friendly enough."