• Exploring targeted strategies for precision delivery, focusing on how route of administration (local/systemic), intracellular trafficking, and endosomal sequestration constrain the translation of oligonucleotide exposure into functional potency
• Preclinical in vivo proof-of-concept data establish a mechanistic framework linking oligonucleotide exposure, endosomal escape, and productive target engagement, independent of target organ or tissue 
• Positioning delivery and endosomal escape as central bottlenecks, we discuss emerging mechanistic insights and translational considerations relevant to CNS-directed applications, emphasizing targeted approaches that improve on-target intracellular availability

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