Delivery of DDRNAI DNA constructs is simplified by the existence of several clinically approved and well-characterized gene therapy vectors developed for the purpose. Delivery is a major challenge for RNAi-based therapeutics with new modifications and reagents continually being developed to optimize target cell delivery. Two broad strategies to facilitate the delivery of DNA constructs to the desired cells are available: these use either viral vectors or one of several classes of transfection reagents.
In vivo delivery of DDRNAI constructs has been demonstrated using a range of vectors and reagents with different routes of administration (ROA).
DDRNAI constructs have also been successfully delivered into host cells ex vivo, and then transplanted back into the host.
For example, in phase I clinical trial at the City of Hope National Medical Center, California, US, four HIV-positive patients with non-Hodgkin's lymphoma were successfully treated with autologous hematopoietic progenitor cells pre-transduced ex vivo with DDRNAI constructs using lentiviral vectors. This construct was designed to express three therapeutic RNAs, one of which was a shRNA, thereby combating HIV replication in three different ways: 
*shRNA, that silences the tat and rev genes of the HIV genome
*CCR5 ribozyme, inhibiting viral cell entry
*TAR decoy RNA, inhibiting initiation of viral transcription.
Ongoing expression of the shRNA has been confirmed in T cells, monocytes, and B cells more than one year after transplantation.