Embodiments of the present disclosure provide novel compositions and methods for making and using thermostable polynucleotide-containing formulations. In certain embodiments, compositions and methods are disclosed for creating thermostable polynucleotides and/or thermostable polynucleotides encoding at least one therapeutic agent for use in therapies for the treatment of health conditions in a subject. In some embodiments, compositions and methods are disclosed for creating thermostable polynucleotides for use in therapeutics, vaccines, and targeted gene therapies. In other embodiments, compositions and methods are disclosed for creating thermostable polynucleotides capable of being coated or encased for prolonged storage and/or timed-delivery.