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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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.

Original languageEnglish
Pages (from-to)917-928
Number of pages12
JournalACS Central Science
Issue number7
Publication statusPublished - 25 Jul 2018


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