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Kupffer cell release of platelet activating factor drives dose limiting toxicities of nucleic acid nanocarriers


Jackson MAMeredith A , Patel SSShrusti S , Yu FFang , Cottam MAMatthew A , Glass EBEvan B , Hoogenboezem ENElla N , Fletcher RBR Brock , Dollinger BRBryan R , Patil PPrarthana , Liu DDDanielle D , Kelly IBIsom B , Bedingfield SKSean K , King ARAllyson R , Miles RERachel E , Hasty AMAlyssa M , Giorgio TDTodd D , Duvall CLCraig L . Biomaterials. 2020 11 23; 268(). 120528


This work establishes that Kupffer cell release of platelet activating factor (PAF), a lipidic molecule with pro-inflammatory and vasoactive signaling properties, dictates dose-limiting siRNA nanocarrier-associated toxicities. High-dose intravenous injection of siRNA-polymer nano-polyplexes (si-NPs) elicited acute, shock-like symptoms in mice, associated with increased plasma PAF and consequently reduced PAF acetylhydrolase (PAF-AH) activity. These symptoms were completely prevented by prophylactic PAF receptor inhibition or Kupffer cell depletion. Assessment of varied si-NP chemistries confirmed that toxicity level correlated to relative uptake of the carrier by liver Kupffer cells and that this toxicity mechanism is dependent on carrier endosome disruptive function. 4T1 tumor-bearing mice, which exhibit increased circulating leukocytes, displayed greater sensitivity to these toxicities. PAF-mediated toxicities were generalizable to commercial delivery reagent in vivo-jetPEI® and an MC3 lipid formulation matched to an FDA-approved nanomedicine. These collective results establish Kupffer cell release of PAF as a key mediator of siRNA nanocarrier toxicity and identify PAFR inhibition as an effective strategy to increase siRNA nanocarrier tolerated dose.