Can the substantiality of phenomena ever be conclusively ruled out through Buddhist practice? I can see how one can develop, through one's practice, a very high degree of confidence in the truth of emptiness through inferring from the conditioned nature of phenomena, their impermanence, their dependence on a perceiving consciousness, and on the need for memory and intelligence in order to recognize them as existent, but is it possible to ever be 100% certain? Who's to say the Higgs Boson isn't the fundamental, truly existent building block of matter that can never be further reduced, even if quantum physics tells us it's in superposition when not interacting with an observer?
Enlightenment happen when knowledge is certain (such knowledge is usually called jñāna), so practice is supposed to provide result as 100% certain knowledge, in regard to what is also required to cease defilements and suffering. Knowledge about 'everything in the World' is not included in that. (Maybe Buddha knows all that, though.)


  Who's to say the Higgs Boson isn't the fundamental, truly existent
  building block of matter that can never be further reduced, even if
  quantum physics tells us it's in superposition when not interacting
  with an observer?


Higgs Boson is a concept. And, as with any concept, we can invent into concepts any idea whatsoever, with any property we can imagine. What is constructed (and thus empty) in Higgs Boson is it's conceptuality, the way how that knowledge is reached.