ArticleCell research2015
Cationic nanocarriers induce cell necrosis through impairment of Na(+)/K(+)-ATPase and cause subsequent inflammatory response.
Article in Cell research, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 140 papers.
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Who cites it
140 citing papers in PubMed, 287 citations in OpenAlex.
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- Biological properties of ceragenin-coated metal nanoparticles - future challenges and perspectives in clinical practice.Nanomedicine (London, England) · 2025Review
- Alveolar Epithelial Cell Dysfunction in Acute Respiratory Distress Syndrome: Mechanistic Insights and Targeted Interventions.Biomedicines · 2025Review
- Harnessing mRNA-lipid nanoparticles as innovative therapies for autoimmune diseases.Molecular therapy. Methods & clinical development · 2025Review
- Nanotechnology for immuno-oncology.Nature cancer · 2025Review
- An injectable hydrogel enhances intratumoral retention and antitumor efficacy of cytokine immunotherapy in murine triple negative breast tumor models.Journal of controlled release : official journal of the Controlled Release Society · 2025Article
80 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
26 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.