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

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

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.

LanguageEnglish
Pages917-928
Number of pages12
JournalACS Central Science
Volume4
Issue number7
DOIs
StatePublished - 25 Jul 2018

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Nanoreactors
Fibroblasts
Shielding
Polyethylene glycols
Carbonates
Enzymes
Cell-Penetrating Peptides
Biodegradability
Antioxidants
Hydration
Catalase
Peptides
Toxicity
Surface treatment
Reactive Oxygen Species
Skin
Cells
Membranes
Oxygen
polycaprolactone

Cite this

van Oppen, Lisanne M.P.E. ; Abdelmohsen, Loai K.E.A. ; van Emst-de Vries, Sjenet E. ; Welzen, Pascal L.W. ; Wilson, Daniela A. ; Smeitink, Jan A.M. ; Koopman, Werner J.H. ; Brock, Roland ; Willems, Peter H.G.M. ; Williams, David S. ; van Hest, Jan C.M./ Biodegradable synthetic organelles demonstrate ROS shielding in human-complex-I-deficient fibroblasts. In: ACS Central Science. 2018 ; Vol. 4, No. 7. pp. 917-928
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abstract = "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.",
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van Oppen, LMPE, Abdelmohsen, LKEA, van Emst-de Vries, SE, Welzen, PLW, Wilson, DA, Smeitink, JAM, Koopman, WJH, Brock, R, Willems, PHGM, Williams, DS & van Hest, JCM 2018, 'Biodegradable synthetic organelles demonstrate ROS shielding in human-complex-I-deficient fibroblasts' ACS Central Science, vol. 4, no. 7, pp. 917-928. DOI: 10.1021/acscentsci.8b00336

Biodegradable synthetic organelles demonstrate ROS shielding in human-complex-I-deficient fibroblasts. / van Oppen, Lisanne M.P.E.; Abdelmohsen, Loai K.E.A.; van Emst-de Vries, Sjenet E.; Welzen, Pascal L.W.; Wilson, Daniela A.; Smeitink, Jan A.M.; Koopman, Werner J.H.; Brock, Roland; Willems, Peter H.G.M.; Williams, David S.; van Hest, Jan C.M.

In: ACS Central Science, Vol. 4, No. 7, 25.07.2018, p. 917-928.

Research output: Contribution to journalArticleAcademicpeer-review

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AU - van Emst-de Vries,Sjenet E.

AU - Welzen,Pascal L.W.

AU - Wilson,Daniela A.

AU - Smeitink,Jan A.M.

AU - Koopman,Werner J.H.

AU - Brock,Roland

AU - Willems,Peter H.G.M.

AU - Williams,David S.

AU - van Hest,Jan C.M.

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van Oppen LMPE, Abdelmohsen LKEA, van Emst-de Vries SE, Welzen PLW, Wilson DA, Smeitink JAM et al. Biodegradable synthetic organelles demonstrate ROS shielding in human-complex-I-deficient fibroblasts. ACS Central Science. 2018 Jul 25;4(7):917-928. Available from, DOI: 10.1021/acscentsci.8b00336