Cationic nanocarriers induce cell necrosis through impairment of Na(+)/K(+)-ATPase and cause subsequent inflammatory response

Cell Res. 2015 Feb;25(2):237-53. doi: 10.1038/cr.2015.9. Epub 2015 Jan 23.


Nanocarriers with positive surface charges are known for their toxicity which has limited their clinical applications. The mechanism underlying their toxicity, such as the induction of inflammatory response, remains largely unknown. In the present study we found that injection of cationic nanocarriers, including cationic liposomes, PEI, and chitosan, led to the rapid appearance of necrotic cells. Cell necrosis induced by cationic nanocarriers is dependent on their positive surface charges, but does not require RIP1 and Mlkl. Instead, intracellular Na(+) overload was found to accompany the cell death. Depletion of Na(+) in culture medium or pretreatment of cells with the Na(+)/K(+)-ATPase cation-binding site inhibitor ouabain, protected cells from cell necrosis. Moreover, treatment with cationic nanocarriers inhibited Na(+)/K(+)-ATPase activity both in vitro and in vivo. The computational simulation showed that cationic carriers could interact with cation-binding site of Na(+)/K(+)-ATPase. Mice pretreated with a small dose of ouabain showed improved survival after injection of a lethal dose of cationic nanocarriers. Further analyses suggest that cell necrosis induced by cationic nanocarriers and the resulting leakage of mitochondrial DNA could trigger severe inflammation in vivo, which is mediated by a pathway involving TLR9 and MyD88 signaling. Taken together, our results reveal a novel mechanism whereby cationic nanocarriers induce acute cell necrosis through the interaction with Na(+)/K(+)-ATPase, with the subsequent exposure of mitochondrial damage-associated molecular patterns as a key event that mediates the inflammatory responses. Our study has important implications for evaluating the biocompatibility of nanocarriers and designing better and safer ones for drug delivery.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Cations / chemistry
  • Cell Line, Tumor
  • Chitosan / chemistry
  • Chitosan / toxicity
  • DNA, Mitochondrial / metabolism
  • Drug Carriers / chemistry
  • Drug Carriers / toxicity*
  • Humans
  • Inflammation / pathology
  • Liposomes / chemistry
  • Liposomes / toxicity
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Myeloid Differentiation Factor 88 / metabolism
  • Nanostructures / chemistry
  • Nanostructures / toxicity*
  • Necrosis*
  • Ouabain / pharmacology
  • Polyethyleneimine / chemistry
  • Polyethyleneimine / toxicity
  • Signal Transduction / drug effects
  • Sodium-Potassium-Exchanging ATPase / antagonists & inhibitors
  • Sodium-Potassium-Exchanging ATPase / genetics
  • Sodium-Potassium-Exchanging ATPase / metabolism*
  • Toll-Like Receptor 9 / metabolism


  • Cations
  • DNA, Mitochondrial
  • Drug Carriers
  • Liposomes
  • Myeloid Differentiation Factor 88
  • TLR9 protein, human
  • Toll-Like Receptor 9
  • Ouabain
  • Polyethyleneimine
  • Chitosan
  • Sodium-Potassium-Exchanging ATPase