Fibrillar nanocarbon-mediated delivery of RNAi therapeutics

S. Alidori, N. Akhavein, D.L.J. Thorek, D.A. Scheinberg, M.R. McDevitt
Memorial Sloan Kettering Cancer Center,
United States

Keywords: RNA interference (RNAi), fibrillar pharmacology, carbon nanotubes, acute kidney injury (AKI)


RNA interference (RNAi) represents one of the most effective ways of developing treatments for undruggable targets. Nonetheless, harnessing the therapeutic potential of RNAi has been a challenge for almost two decades that has yet to be fulfilled. Thus far, clinical RNAi formulations are limited to topical administration for age-related macular degeneration and respiratory syncitial virus infection, as systemic delivery is needed to address major unmet medical needs. The formulation of small interfering RNA (siRNA) with different nanoparticles has been investigated in order to mediate transport to specific tissue of interest, while preventing RNA degradation. Several nanoparticle-based siRNA therapeutics have already entered clinical trials, including lipid nanoparticles and cyclodextrines. Other nanoplatforms such as polymeric nanoparticles, polyethyleneimine, chitosan, polylactic/glycolic acid-based nanoparticles, quantum dots, iron oxide and gold nanoparticles, and carbon nanotubes are currently being evaluated for siRNA delivery. In this work we exploited functionalized fibrillar nanocarbon (fCNT) as a novel platform that facilitated specific delivery of target siRNA to renal proximal tubule cells via systemic administration and achieved prophylactic prevention of acute kidney injury in animal models. fCNT-delivered siRNA not only prevented renal injury and improved progression-free survival following a nephrotoxic insult, but also reduced the occurrence of fibrosis and immune cell infiltration. This result together with a preliminary evaluation in non-human primates suggested that the fibrillar nanocarbon-mediated delivery of siRNA could be used as preventive therapy for AKI in anticipation of a nephrotoxic or ischemic medical intervention.