The extremely low-efficient cytosolic release of the internalized siRNA has been emerged recently as a central issue for siRNA delivery, while there is a lack of guideline to facilitate the cytosolic release of internalized siRNA. To address the concern, we studied the contribution of pH-sensitive inner core on handling the cytosolic release of siRNA delivered by a series of PG-P(DPAx-co-DMAEMAy)-PCB amphiphilic polycation nanomicelles (GDDC-Ms) with extremely low internalization (<1/4 of Lipofactamine 2000 (Lipo2000)). Significantly, just by varying the mole ratio of DPA and DMAEMA to adjust the initial disassembly pH (pHdis) of the core near to 6.8, GDDC4-Ms/siRNA could get nearly 98.8% silencing efficiency at w/w=12 with 50 nM siRNA and ~78% silencing efficiency at w/w=30 with very low dose of 5 nM siRNA in HepG-2 cell lines, while Lipo2000 only got 65.7% with 50 nM siRNA. Furthermore, ~98.4% silencing efficiency was also realized in the hard-to-transfect human acute monoblastic leukemia cell line U937 by GDDC4-Ms/siRNA (at w/w=15, 50 nM siRNA), in the inefficient case for Lipo2000. And the high silencing efficiency (~80%) in skin tissue in vivo was discovered. Undoubtedly, the robust potential of GDDC4-Ms in handling the cytosolic release paves a simple but efficient new way for the design of the non-viral siRNA vector.
Keywords: cytosolic release • low internalization • low doses• high efficiency • siRNA delivery • monoblastic cell