A Synthetic Protocell-Based Heparin Scavenger.

Heparin is a commonly applied blood anticoagulant agent in clinical use. After treatment, excess heparin needs to be removed to circumvent side effects and recover the blood-clotting cascade. Most existing heparin antidotes rely on direct heparin binding and complexation, yet selective compartmentalization and sequestration of heparin would be beneficial for safety and efficiency. However, such systems have remained elusive. Herein, a semipermeable protein-based microcompartment (proteinosome) is loaded with a highly positively charged chitosan derivative, which can induce electrostatics-driven internalization of anionic guest molecules inside the compartment. Chitosan-loaded proteinosomes are subsequently employed to capture heparin, and an excellent heparin-scavenging performance is demonstrated under physiologically relevant conditions. Both the highly positive scavenger and the polyelectrolyte complex are confined and shielded by the protein compartment in a time-dependent manner. Moreover, selective heparin-scavenging behavior over serum albumin is realized through adjusting the localized scavenger or surrounding salt concentrations at application-relevant circumstances. In vitro studies reveal that the cytotoxicity of the cationic scavenger and the produced polyelectrolyte complex is reduced by protocell shielding. Therefore, the proteinosome-based systems may present a novel polyelectrolyte-scavenging method for biomedical applications.

[1]  S. Mann,et al.  Triggerable Protocell Capture in Nanoparticle-Caged Coacervate Microdroplets , 2022, Journal of the American Chemical Society.

[2]  D. Qiu,et al.  A three-tiered colloidosomal microreactor for continuous flow catalysis , 2021, Nature Communications.

[3]  M. Kostiainen,et al.  Polyelectrolyte Encapsulation and Confinement within Protein Cage-Inspired Nanocompartments , 2021, Pharmaceutics.

[4]  Yan Qiao,et al.  Directing Transition of Synthetic Protocell Models via Physicochemical Cues‐Triggered Interfacial Dynamic Covalent Chemistry , 2021, Advanced science.

[5]  Jianzhong Wu,et al.  Membrane-confined liquid-liquid phase separation toward artificial organelles , 2021, Science Advances.

[6]  Zhuojun Meng,et al.  Cationic cellulose nanocrystals for fast, efficient and selective heparin recovery , 2021 .

[7]  J. V. van Hest,et al.  Engineering of Biocompatible Coacervate-Based Synthetic Cells , 2021, ACS applied materials & interfaces.

[8]  Kemin Wang,et al.  Enzyme-mediated nitric oxide production in vasoactive erythrocyte membrane-enclosed coacervate protocells , 2020, Nature Chemistry.

[9]  D. Hilvert,et al.  Two-tier supramolecular encapsulation of small molecules in a protein cage , 2020, Nature Communications.

[10]  Yuval Elani,et al.  Interfacing Living and Synthetic Cells as an Emerging Frontier in Synthetic Biology , 2020, Angewandte Chemie.

[11]  Stephen Mann,et al.  Light-Activated Signaling in DNA-Encoded Sender–Receiver Architectures , 2020, bioRxiv.

[12]  M. Nowakowska,et al.  Heparin-Binding Copolymer as a Complete Antidote for Low-Molecular-Weight Heparins in Rats , 2020, The Journal of Pharmacology and Experimental Therapeutics.

[13]  L. Gurevich,et al.  Drug Delivery with Polymeric Nanocarriers—Cellular Uptake Mechanisms , 2020, Materials.

[14]  V. Linko,et al.  Serum Albumin–Peptide Conjugates for Simultaneous Heparin Binding and Detection , 2019, ACS omega.

[15]  S. Mann,et al.  Response-retaliation behaviour in synthetic protocell communities. , 2019, Angewandte Chemie.

[16]  S. Mann,et al.  Spatial Positioning and Chemical Coupling in Coacervate‐in‐Proteinosome Protocells , 2019, Angewandte Chemie.

[17]  A. Patil,et al.  Modulation of Higher‐order Behaviour in Model Protocell Communities by Artificial Phagocytosis , 2019, Angewandte Chemie.

[18]  Stephen Mann,et al.  DNA-based Communication in Populations of Synthetic Protocells , 2019, Nature Nanotechnology.

[19]  J. V. van Hest,et al.  Feedback-Induced Temporal Control of “Breathing” Polymersomes To Create Self-Adaptive Nanoreactors , 2018, Journal of the American Chemical Society.

[20]  Stephen Mann,et al.  Predatory behaviour in synthetic protocell communities. , 2017, Nature chemistry.

[21]  O. Rojas,et al.  Effect of PEG-PDMAEMA Block Copolymer Architecture on Polyelectrolyte Complex Formation with Heparin. , 2016, Biomacromolecules.

[22]  R. Linhardt,et al.  Heparin: Past, Present, and Future , 2016, Pharmaceuticals.

[23]  B. Kalaska,et al.  The toxicology of heparin reversal with protamine: past, present and future , 2016, Expert opinion on drug metabolism & toxicology.

[24]  Christopher M. Jakobson,et al.  Influence of Electrostatics on Small Molecule Flux through a Protein Nanoreactor. , 2015, ACS synthetic biology.

[25]  J. Bereta,et al.  Nonclinical Evaluation of Novel Cationically Modified Polysaccharide Antidotes for Unfractionated Heparin , 2015, PloS one.

[26]  A. Patil,et al.  Design and construction of higher-order structure and function in proteinosome-based protocells. , 2014, Journal of the American Chemical Society.

[27]  David K. Smith,et al.  Heparin sensing and binding - taking supramolecular chemistry towards clinical applications. , 2013, Chemical Society reviews.

[28]  Stephen Mann,et al.  Interfacial assembly of protein–polymer nano-conjugates into stimulus-responsive biomimetic protocells , 2013, Nature Communications.

[29]  V. Trezza,et al.  Human serum albumin: from bench to bedside. , 2012, Molecular aspects of medicine.

[30]  David K Smith,et al.  Self-assembling ligands for multivalent nanoscale heparin binding. , 2011, Angewandte Chemie.

[31]  Gaurav Sahay,et al.  Endocytosis of nanomedicines. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[32]  M. Nowakowska,et al.  Chitosan derivatives as novel potential heparin reversal agents. , 2010, Journal of medicinal chemistry.

[33]  Olli Ikkala,et al.  Precisely defined protein-polymer conjugates: construction of synthetic DNA binding domains on proteins by using multivalent dendrons. , 2007, ACS nano.

[34]  A. Girolami,et al.  Heparin-induced thrombocytopenia: a review. , 2006, Seminars in thrombosis and hemostasis.

[35]  J. Hardy,et al.  High-affinity multivalent DNA binding by using low-molecular-weight dendrons. , 2005, Angewandte Chemie.

[36]  S. Hudson,et al.  Synthesis and antimicrobial activity of a water-soluble chitosan derivative with a fiber-reactive group. , 2004, Carbohydrate research.

[37]  Robert J Linhardt,et al.  Characterization of heparin binding by a peptide from amyloid P component using capillary electrophoresis, surface plasmon resonance and isothermal titration calorimetry. , 2002, European journal of biochemistry.

[38]  Trevor Douglas,et al.  Host–guest encapsulation of materials by assembled virus protein cages , 1998, Nature.