摘要：SummaryThe therapeutic use of RNAi has grown but often faces several hurdles related to delivery systems, compound stability, immune activation, and on-target/off-tissue effects. Self-delivering RNAi (sdRNA) molecules do not require delivery agents or excipients. Here we demonstrate the ability of sdRNA to reduce the expression of PTEN (phosphatase and tensin homolog) to stimulate regenerative axon regrowth in the injured adult CNS. PTEN-targeting sdRNA compounds were tested for efficacyin vivoby intravitreal injection after adult rat optic nerve injury. We describe critical steps in lead compound generation through the optimization of nucleotide modifications, enhancements for stability in biological matrices, and screening for off-target immunostimulatory activity. The data show that PTEN expressionin vivocan be reduced using sdRNA and this enhances regeneration in adult CNS neurons after injury, raising the possibility that this method could be utilized for other clinically relevant nervous system indications.Graphical abstractDisplay OmittedHighlights•self-delivering siRNA (sdRNA) can decrease neuronal gene expressionin vivo•sdRNA can be successfully deliveredin vivowithout using vectors or excipients•Phosphatase and tensin homolog (PTEN)-targeting sdRNA can enhance CNS neuronal regeneration after injuryBiotechnology; Health sciences; Techniques in neuroscience.
