Perturbation of Cellular Redox Homeostasis Dictates Divergent Effects of Polybutyl Cyanoacrylate (PBCA) Nanoparticles on Autophagy

Cells. 2021 Dec 6;10(12):3432. doi: 10.3390/cells10123432.


Nanoparticles (NPs) are used in our everyday life, including as drug delivery vehicles. However, the effects of NPs at the cellular level and their impacts on autophagy are poorly understood. Here, we demonstrate that the NP drug delivery vehicle poly(butyl cyanoacrylate) (PBCA) perturbs redox homeostasis in human epithelial cells, and that the degree of redox perturbation dictates divergent effects of PBCA on autophagy. Specifically, PBCA promoted functional autophagy at low concentrations, whereas it inhibited autophagy at high concentrations. Both effects were completely abolished by the antioxidant N-acetyl cysteine (NAC). High concentrations of PBCA inhibited MAP1LC3B/GABARAP lipidation and LC3 flux, and blocked bulk autophagic cargo flux induced by mTOR inhibition. These effects were mimicked by the redox regulator H2O2. In contrast, low concentrations of PBCA enhanced bulk autophagic cargo flux in a Vps34-, ULK1/2- and ATG13-dependent manner, yet interestingly, without an accompanying increase in LC3 lipidation or flux. PBCA activated MAP kinase signaling cascades in a redox-dependent manner, and interference with individual signaling components revealed that the autophagy-stimulating effect of PBCA required the action of the JNK and p38-MK2 pathways, whose activities converged on the pro-autophagic protein Beclin-1. Collectively, our results reveal that PBCA exerts a dual effect on autophagy depending on the severity of the NP insult and the resulting perturbation of redox homeostasis. Such a dual autophagy-modifying effect may be of general relevance for redox-perturbing NPs and have important implications in nanomedicine.

Keywords: autophagy; nanoparticle; oxidative stress; p38; poly(alkyl cyanoacrylate).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / metabolism
  • Acetylcysteine / pharmacology
  • Antioxidants / metabolism
  • Antioxidants / pharmacology
  • Autophagy / drug effects*
  • Autophagy / genetics
  • Autophagy-Related Protein-1 Homolog / genetics
  • Autophagy-Related Proteins / genetics
  • Beclin-1 / genetics
  • Class III Phosphatidylinositol 3-Kinases / genetics
  • Drug Delivery Systems*
  • Enbucrilate / chemistry
  • Enbucrilate / pharmacology*
  • Epithelial Cells / drug effects
  • Gene Expression Regulation / drug effects
  • Homeostasis / drug effects
  • Humans
  • Hydrogen Peroxide / metabolism
  • Hydrogen Peroxide / pharmacology
  • MAP Kinase Kinase 4 / genetics
  • Nanoparticles / chemistry*
  • Oxidation-Reduction / drug effects
  • p38 Mitogen-Activated Protein Kinases / genetics


  • ATG13 protein, human
  • Antioxidants
  • Autophagy-Related Proteins
  • Beclin-1
  • Hydrogen Peroxide
  • Class III Phosphatidylinositol 3-Kinases
  • Autophagy-Related Protein-1 Homolog
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4
  • Enbucrilate
  • Acetylcysteine