abstract
Silk fibroin nanoparticles are emerging as promising nanomedicines, but their full therapeutic potential is yet to be realized. These nanoparticles can be readily PEGylated to improve colloidal stability and to tune degradation and drug release profiles; however, the relationship between silk fibroin nanoparticle PEGylation and macrophage activation still requires elucidation. Here, we used in vitro assays and nuclear magnetic resonance based metabolomics to examine the inflammatory phenotype and metabolic profiles of macrophages following their exposure to unmodified or PEGylated silk fibroin nanoparticles. The macrophages internalized both types of nanoparticles, but they showed different phenotypic and metabolic responses to each nanoparticle type. Unmodified silk fibroin nanoparticles induced the upregulation of several processes, including production of proinflammatory mediators (e.g., cytokines), release of nitric oxide, and promotion of antioxidant activity. These responses were accompanied by changes in the macrophage metabolomic profiles that were consistent with a proinflammatory state and that indicated an increase in glycolysis and reprogramming of the tricarboxylic acid cycle and the creatine kinase/phosphocreatine pathway. By contrast, PEGylated silk fibroin nanoparticles induced milder changes to both inflammatory and metabolic profiles, suggesting that immunomodulation of macrophages with silk fibroin nanoparticles is PEGylation-dependent. Overall, PEGylation of silk fibroin nanoparticles reduced the inflammatory and metabolic responses initiated by macrophages, and this observation could be used to guide the therapeutic applications of these nanoparticles.
keywords
TUMOR-ASSOCIATED MACROPHAGES; NITRIC-OXIDE; ACTIVATED MACROPHAGES; IN-VITRO; HEMOCOMPATIBILITY; BIOCOMPATIBILITY; COLOCALIZATION; PRINCIPLES; SUCCINATE; DESIGN
subject category
Science & Technology - Other Topics; Materials Science
authors
Totten, JD; Wongpinyochit, T; Carrola, J; Duarte, IF; Seib, FP
our authors
Iola Melissa Fernandes Duarte
Principal Researcher
Joana Carolina Quintela Carrola
PhD Studentacknowledgements
The University of Strathclyde supported this study with a Research and Development Grant 1715 (F.P.S, I.F.D.). J.D.T.'s Ph.D. studentship is sponsored by the EPSRC Doctoral Training Partnership (EP/M508159/1), University of Strathclyde. The authors thank the International Strategic Partnership between the University of Strathclyde and Nanyang Technological University, Singapore for funding Ph.D. candidate T.W. The work was also developed in the scope of the project CICECO-Aveiro Institute of Materials, FCT Ref. UID/CTM/50011/2019, financed by national funds through the FCT/MCTES. The authors also acknowledge the Portuguese National NMR (PTNMR) Network, supported with FCT funds, and the European Union Framework Programme for Research and Innovation HORIZON 2020, under the TEAMING Grant agreement No 739572 - The Discoveries CTR. I.F.D. further acknowledges FCT/MCTES for a research contract under the Program Investigador FCT 2014.