What is the largest roadblock scientists face in devising a theory of everything?

Maybe the single most prominent snag is that cutting edge science - by definition - must be sought after under the domain of the truth worldview that has governed each such mainstream endeavor at deciding the genuine idea of all that is physical and accordingly real. That worldview states that except if it is material in structure [a particle], or is the net consequence of a relationship dynamic between at least two material structures [a power or field], at that point it doesn't exist as physical or genuine.

Obviously, this leads every taught exertion to "rundown" each line of auxiliary dynamic advancement [reductionism] into a hypothetical block divider, paying little heed to how smart a scholar may be at parsing his/her depictions of what may/must be at the establishment of said formative line. The presence of framework inclinations alone remains a puzzle that will never be appropriately clarified - experimentally - by any ToE scholar because of this one overriding worldview definition that lone material structure [and relationship elements between material structures] can be inspected as science.

This strident refusal to take into consideration the physical presence of non-material objectives and initiators [a contentious social aftereffect from hundreds of years of mystery's rule over all issues concerning the bigger idea of the real world and humankind's place inside it] will keep on vexing all endeavors to precisely figure out what is genuine, why reality has advanced as it has, and what lies at the establishment of every one of that exists as physical/real.

Tragically, even the affirmation that such non-material facts must exist as physical organizations [due to the legitimate dismissal of "turtles right down" vast regression] promptly marks that affirmation as pseudoscientific in nature.

In all actuality except if a hypothesis can really clarify the key idea of what lies at the premise of everything that has [and will] rise/develop as genuine, that hypothesis may be helpful or pertinent inside a particular performance center of progressing exertion [transactional], however it is anything but a hypothesis of everything.