Independent effect of polymeric nanoparticle zeta potential /surface charge, on their cytotoxicity and affinity to cells

Significance Statement

Nanoparticles have shown great potentials in drug delivery, diagnosis and therapeutics. However, comprehensive understanding of the effect of nanoparticle zeta potential on its interaction with cells is still lack although such interaction has substantial impacts on nanoparticles efficacy. In this present work, we aim to investigate how nanoparticle zeta potential affects its cytotoxicity and disclose the underlying mechanisms by quantifying the interaction force between cells and nanoparticles via atom force microscopy (AFM). Four kinds of nanoparticles that possessed similar sizes around 230 nm and gradient zeta potentials ranging from -30 mv to +40 mv were fabricated. The cytotoxicity of these nanoparticles was found to be zeta potential-dependent. The nanoparticles  possessing positive surface charges were more toxic than negative nanoparticles, and the nanoparticles possessing higher like charges led to higher cytotoxicity. AFM showed that the positively charged nanoparticles or the nanoparticles with higher like charges had significantly higher interaction force to cells. The interaction force indicated the affinity to cells and could be the main reason of nanoparticles to induce cytotoxicity. This is the first report investigating the independent effect of nanoparticles zeta potential on its cytotoxicity and cellular affinity. Our findings suggest that in practical application, negative nanoparticles would be better for delivering general agents for diagnosis and therapy. On the other hand, positive nanoparticles would be better for delivering anti-tumor agents for chemotherapy. This work proposes a novel approach to investigate the cellular affinity of nanoparticles and demonstrates the importance of controlling zeta potential in practical use of nanoparticles.

About the author

Yunfeng Lin, D.D.S., M.D., Ph.D., is Professor of State Key Laboratory of Oral Diseases, Sichuan University. He serves as the Vice-director of State Key Laboratory of Oral Diseases and Assistant Dean of West China School of Stomatology. He received his Ph.D. from Sichuan University in 2006. Dr. Lin’s research focus on adipose stem cells, biomaterials and craniofacial regeneration, such as bone, cartilage, tooth, fat et al. He has published over 100 papers, reviews and book chapters, and made several seminal contributions to the stem cells fields. He received Young scientific and technological innovation leader of China, Chinese Youth Science and Technology Award, Ministry of Education Science and Technology Progress Award, Henry Fok prize for young teachers in Colleges and Universities, New Century Excellent Talents of Chinese Ministry of Education and National Excellent Doctoral Dissertation of China.

About the author

Dr. Peng received his PhD from Sichuan University (Chengdu, China) in 2012 and was appointed as a lecturer in Sichuan University in the same year and promoted as an associate professor in 2014. He studied in Keele University (Stoke-On-Trent, UK) as an exchange PhD student from 2010 to 2011 and researched in University of Copenhagen (Copenhagen, Denmark) as a visiting scholar in 2015. His research interests are biomaterials and drug delivery. He currently focuses on the interactions between nanoparticles and proteins/cells. He has received the Sichuan Provincial Award of Outstanding PhD Dissertation in 2013 and the First Prize of Chinese Outstanding Young Investigator Award (IADR-China Division) in 2014.  

Global Medical Discovery polymeric nanoparticle zeta potential

Journal Reference

Cell Prolif. 2015 ;48(4):465-74. 

Shao XR1, Wei XQ1, Song X2, Hao LY1, Cai XX1, Zhang ZR2, Peng Q1, Lin YF1.

[expand title=”Show Affiliations”]
  1. State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
  2. Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.



Up to now, little research has been focussed on discovering how zeta potential independently affects polymeric nanoparticle (NP) cytotoxicity.


Polymeric nanoparticles of gradient zeta potential ranging from -30 mv to +40 mv were fabricated using the same poly-3-hydroxybutyrate-co-3-hydroxyhexanoate (PHBHHx) biopolymer. Interaction forces between nanoparticles and cells were measured by atomic force microscopy (AFM). Cytotoxicity of the nanoparticles to cells was investigated by using MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide) assay.


Four kinds of nanoparticle with similar sizes and gradient zeta potentials, were fabricated. Those with positive surface charges were found to be more toxic than those with negative surface charges. Positively charged nanoparticles or nanoparticles with higher ‘like’ charges, offered higher interaction force with cells.


This work proposes a novel approach for investigating interaction between NPs and cells, and discloses the importance of controlling zeta potential in developing NPs-based formulations in the future.

© 2015 John Wiley & Sons Ltd.

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