Abstract: Among other things, the present disclosure provides oligonucleotides, compositions, and methods for preventing and/or treating various conditions, disorders or diseases. In some embodiments, provided technologies comprise nucleobase modifications, sugar modifications, internucleotidic linkage modifications and/or patterns thereof, and have improved properties, activities and/or selectivities. In some embodiments, provided technologies target MAPT. In some embodiments, the present disclosure provides MAPT oligonucleotides, compositions and methods for preventing and/or treating MAPT-associated conditions, disorders or diseases, such as Alzheimer's Disease (AD) or Frontotemporal Dementia (FTD).