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Abstract Traumatic brain injury (TBI) impacts millions of people globally, however currently there are no approved therapeutics that address long‐term brain health. In order to create a technology that is relevant for siRNA delivery in TBI after systemic administration, sub‐100 nm nanoparticles with rolling circle transcription (RCT) are synthesized and isolated in order improve payload delivery into the injured brain. Unlike conventional RCT‐based RNA particles, in this method, sub‐100 nm RNA nanoparticles (RNPs) are isolated. To enhance RNP pharmacokinetics, RNPs are synthesized with modified bases in order to graft polyethylene glycol (PEG) to the RNPs. PEGylated RNPs (PEG‐RNPs) do not significantly impact their knockdown activity in vitro and lead to longer blood half‐life after systemic administration and greater accumulation into the injured brain in a mouse model of TBI. In order to demonstrate RNA interference (RNAi) activity of RNPs, knockdown of the inflammatory cytokine TNF‐α in injured brain tissue after systemic administration of RNPs in a mouse model of TBI is demonstrated. In summary, small sub‐100 nm multimeric RNA nanoparticles are synthesized and isolated that can be modified using accessible chemistry in order to create a technology suitable for systemic RNAi therapy for TBI.