title: SiRNA Crosslinked Nanoparticles for the Treatment of Inflammation-induced Liver Injury.
abstract: RNA interference mediated by small interfering RNA (siRNA) provides a powerful tool for gene regulation, and has a broad potential as a promising therapeutic strategy. However, therapeutics based on siRNA have had limited clinical success due to their undesirable pharmacokinetic properties. This study presents pH-sensitive nanoparticles-based siRNA delivery systems (PNSDS), which are positive-charge-free nanocarriers, composed of siRNA chemically crosslinked with multi-armed poly(ethylene glycol) carriers via acid-labile acetal linkers. The unique siRNA crosslinked structure of PNSDS allows it to have minimal cytotoxicity, high siRNA loading efficiency, and a stimulus-responsive property that enables the selective intracellular release of siRNA in response to pH conditions. This study demonstrates that PNSDS can deliver tumor necrosis factor alpha (TNF-α) siRNA into macrophages and induce the efficient down regulation of the targeted gene in complete cell culture media. Moreover, PNSDS with mannose targeting moieties can selectively accumulate in mice liver, induce specific inhibition of macrophage TNF-α expression in vivo, and consequently protect mice from inflammation-induced liver damages. Therefore, this novel siRNA delivering platform would greatly improve the therapeutic potential of RNAi based therapies.
authors.affiliation: Innovative Drug Research Center Chongqing University Chongqing 401331 P. R. China.
authors.forename: Yaqin
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Innovative Drug Research Center Chongqing University Chongqing 401331 P. R. China.
authors.forename: Ziying
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: Innovative Drug Research Center Chongqing University Chongqing 401331 P. R. China.
authors.forename: Xiao
authors.initials: X
authors.lastname: He
authors.affiliation: Innovative Drug Research Center Chongqing University Chongqing 401331 P. R. China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Biomedical Engineering Nanjing University Nanjing 210093 P. R. China.
authors.forename: Xinghai
authors.initials: X
authors.lastname: Ning
authors.affiliation: Innovative Drug Research Center Chongqing University Chongqing 401331 P. R. China.
authors.forename: Xuli
authors.initials: X
authors.lastname: Feng
keywords: acid labile; copper free click; positive‐charge‐free; siRNA crosslinking; targeting