Biodegradable synthetic organelles demonstrate ROS shielding in human-complex-I-deficient fibroblasts

Lisanne M.P.E. van Oppen, Loai K.E.A. Abdelmohsen, Sjenet E. van Emst-de Vries, Pascal L.W. Welzen, Daniela A. Wilson, Jan A.M. Smeitink, Werner J.H. Koopman, Roland Brock, Peter H.G.M. Willems, David S. Williams, Jan C.M. van Hest

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74 Citaten (Scopus)
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Samenvatting

Biodegradable, semipermeable nanoreactors that are capable of undergoing cellular integration and, subsequently, function as synthetic organelles represent an exciting therapeutic technology. Polymersomal nanoreactors have been investigated as a suitable candidate for the engineering of such a system, with the chemical versatility and structural robustness required for such a demanding application. Although steps have been taken to demonstrate this capacity, there has yet to be a system presented with biochemically robust data showing therapeutic efficacy in primary human cells. The reason for this shortfall is the absence of essential criteria of the polymersomes tested so far; biodegradability, intrinsic semipermeability, and a biomedically relevant setting. Herein, we present enzyme-loaded, biodegradable poly(ethylene glycol)-block-poly(caprolactone-gradient-trimethylene carbonate) (PEG-PCLgTMC) polymersomal nanoreactors, readily fabricated using the biocompatible direct hydration methodology. Physical characterization of PEG-PCLgTMC polymersomes highlights their semipermeable membrane and ability to shield enzymatic cargo. Surface modification with cell-penetrating peptides (CPPs) directs cellular integration of enzyme-loaded PEG-PCLgTMC nanoreactors in a controlled fashion. Using HEK293T cells and human skin fibroblasts we demonstrate that biocompatible catalase nanoreactors successfully perform as a synthetic organelle, imparting activity-dependent antioxidant (reactive-oxygen-species-shielding, ROS-shielding) capacity to cells. Notably, for the first time, patient-derived human-complex-I-deficient primary fibroblasts are effectively protected against the toxicity of exogenous H2O2 by the action of internalized enzyme-loaded nanoreactors, showcasing this system in a therapeutically relevant context.

Originele taal-2Engels
Pagina's (van-tot)917-928
Aantal pagina's12
TijdschriftACS Central Science
Volume4
Nummer van het tijdschrift7
DOI's
StatusGepubliceerd - 25 jul. 2018

Financiering

The authors would like to thank Paul White (Radboud University, Nijmegen) for assistance with NOESY NMR measurements. We would also like to thank Joep van der Weijden and Melek Parlak for assistance with CPP modification of polymersomes and peptide synthesis, respec- tively. This work was supported by the Dutch Ministry of Education, Culture and Science (Gravitation program 024.001.035), the ERC Advanced Grant Artisym 694120, NWO Chemische Wetenschappen VIDI Grant 723.015.001, and the Radboud Nanomedicine Alliance. We thank the Ser Cymru II programme for support of D.S.W.; this project received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie Grant Agreement 663830.

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