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Protocells: A promising new platform

Figuring out the origin of life has been a lifelong goal of humanity, and research has been going on for as long as humanity has existed. Surprisingly, this research into how the first cells were formed have an interesting topic in common with research in novel methods of drug delivery, microbioreactors and tissue engineering: protocells. Protocells are defined as “hypothetical precursor structures of the first cells, which are assumed to have been formed at the origin of life”.(1) Due to them existing in a timeframe before cells, they are “structurally and organizationally simpler” than them and are “composed of chemical components that do not require living systems for their synthesis”.(1) While these protocells are a prominent candidate to how the first cells were formed, it is also becoming a popular research topic as a means of creating a synthetic cell like structure that can be utilized in multiple ways.

Since the definition of a protocell is fairly vague, there are a variety protocell models the researchers have envisaged. One of the most prominent is a protocell model based on colloidosomes. (2) Colloidosomes are “microscale capsules that are produced from the spontaneous self-assembly of inorganic or organic colloidal particles in water/oil biphasic systems”, where the “assembly is driven by a decrease in total free energy associated with placement of the particles specifically at the liquid/liquid interface and produces stabilizes water or oil droplets”.(2) These particles between the oil and water surfaces, such as silica and calcium carbonate can act as pores that have high selective permeability based on solute size exclusion.(2–4) This makes it a potential candidate for macromolecular storage and for controlling matter transport between microscale environments.(2) However colloidosomes have trouble regulating small molecules through the colloidosome monolayer over a broad range of membrane particle diameters, making it hard to use them as a tool to rapidly discharge small molecules into its environment.(2,5) A possible solution to this was studied in a paper by Li et al. where the inter-surface particles where modified so that the outer membrane could electrostatically mediate the diffusion of small molecules through the interstitial nano space of the particles.(2,6) Another challenge faced by most inorganic synthetic protocells is the issue of growth and replication. A study by the same author studied this topic further, finding the possibility of using organosilane-mediated methanol formation inside of the protocells to rupture the membrane and thus “replicating” itself.(2,7) With these potential solutions to its problems, colloidosome based protocells could be a viable option for a novel method of drug delivery while being able to spontaneously replicate itself when needed.

Another model attracting attention is the proteinsome based protocell. These protocells are based on the “spontaneous interfacial assembly of amphiphilic protein-polymer nano-conjugates”, where proteinsomes are protein-polymer nano-conjugates that “are assembled at water droplet/oil interfaces into micrometer0scale water filled capsules”.(2,8) Notably, this protocell model was able to ”entrap a hundred or so components of a cell-free gene expression system within the proteinsome internal volume and perform in situ protein synthesis” as well as being “sufficiently elastic and robust to withstand partial dehydration and rehydration, and remained structurally intact when held at a temperature of 70°C for 90min”.(2) These properties make proteinsome based protocells an excellent candidate for microscale confinement of thermophilic enzymes as well as developing synthetic cells that are able to go through temperature cycling procedures such as PCR.(2) Another advantage of proteinsomes is that their structure and function can be designed by manipulating the protein-polymer nano-conjugate building blocks.(2) A study by Huang et al. showed that proteinsome based protocells could be semi-permeable, stimulus-responsive, enzymatically active, and mechanically elastic. (2,8) Another study by Huang et al. looked into the enabling higher order functionality in the protocells.(2,9) Genetic polymers were encapsulated in the proteinsomes as well as generating supramolecular amino acid hydrogel using enzyme mediated amino acid dephosphorylation which resulted in the mechanical properties of the protocell being enhanced.(2,9) Similar to colloidosome based protocells, proteinsome based protocells offer high modularity which could be utilized by researchers to create a variety of use cases.

Other than colloidosomes and proteinsomes, polymerases are also used as a protocell model. Compared to the above mentioned models, polymersome based protocells are composed of self-assembled amphiphilic block copolymers that are arranged into vesicle like micro architectures, making them more in line with conventional cells.(2) Polymersome are generally considered to be more stable than liposomes from conventional cells, and can be prepared with a variety of membrane chemistries to give it features such as semi-permeability.(2,10,11) For example, a study by Kumar et al. found that “channel forming proteins could be reconstituted without loss of function within the polymer membrane to produce polymersomes with size-selective or substrate selective pores”.(3,10) Another study by Kim et al. looked at the controlling the permeability of the polymersome by using a mixture of amphiphilic and stimuli-responsive block copolymers, as well as inducing protocell disassembly and regulating enzymes within in accordance to the environment.(11) One study by Peters et al. examined the possibility of multi-compartmentalization in polymersomes by loading functional organelle mimics inside a larger polymersome, where incompatible enzymes were separately compartmentalized to retain functionality.(12) While this model does offer similarities to conventional cells, the increased stability and possibility for added functionality make this model another promising platform for various uses.

The last notable protocell model is the hybrid protocell. In this model, “membrane-bound coacervate micro-droplets” were use that were prepared using “spontaneous assembly or partitioning of auxiliary components on the surface of the liquid microcompartments”. In a paper by Tang et al., a-snilionoapthalene-8-sulphonic acid (ANS) was used with positively charged oligosyline/ATP coacervate microdroplets, which resulted in the formation of a thin outer shell that was “mechanically more compliant than the droplet interior”.(2,13) In another paper by Williams et al., a “molecularly crowded, polyelectrolyte/ribonucleotide-enriched coacervate droplets can be transformed into membrane-bounded vesicles by using a polyoxometalate-mediated surface-templating procedure”, where the proteins encased in the coacervate vesicles could be utilized for the coupling of enzyme cascade reactions.(2,14) While this model is not as modular as the above mentioned models, these hybrid protocells can be utilized for “membrane-compartmentalization, chemical enrichment and molecular crowding” through simple physical and chemical processes, making them useful in specific scenarios.(2)

With the advancements in protocell research, scientists have been able to utilize them in many fields. For example, a paper by Rodríguez-Arco et al sought to create “micro-compartmentalized colloidal objects as a model of a synthetic protocell community exhibiting a rudimentary form of artificial phagocytosis based on controlled engulfment”, where phagocytosis is a process were cells take up external objects.(15) The entire process was done in dodecane, containing iron oxide particle stabilized water-in-oil magnetic Pickering emulsion(MPE) droplets.(15) By exploiting the fact that the MPE droplets could be opened up with oleate, synthetic phagocytosis was performed onto target crosslinked silica colloidosomes.(15) When the colloidosomes, whatever they were carrying was also released into the aqueous interior of the MPE droplet, making them a potential platform for drug delivery if the MPE droplets could then be opened up at a specific points.(15) The paper also mentions the possibility of using these protocells as a functional microscale system, similar to how traditional cells communicate and function with each other. In another study by Gobbo et al looked at a “programmed assembly of spatially integrated prototissue spheroids that comprise a binary community of bio-orthogonally linked proteinsome-based protocells capable of thermoresponsive collective behaviours”.(16) Two new types of thermoresponsive proteins, N3-BSA/poly(N-isopropylacrylamide-co-methacrylic acid)(PNIPAM-co-MAA) and BCN-BSA/PNIPAM-co-MAA nanoconjugates, were made specifically for this study.(16) Since these proteinsome spheroids were shown to contract and expand under certain temperature conditions, a system was created where tissue-like constructs capable of reversible and sustainable contractions that were enzymatically modulated and exploited for mechanochemical transduction of a proteinsome-coordinated enzyme cascade.(16) The finding indicate the possibility for enzymatically active tissue like structures capable of internalized protocell-protocell communication and sensing of chemical stimuli in the surrounding environment. In addition, this research could be utilized in multiple fields such as tissue engineering, drug delivery, signalling, gene regulation and bioreactor technology.(16)

Advancements in protocell research have shown that it is indeed a very promising platform that can be utilized in many ways. The various protocell models, such as colloidosomes, proteinsomes, polymersomes and hybrid based protocell models all offer a unique advantage that could make them useful in various areas such as drug delivery, microscale confinement of thermoresponsive enzymes and microreactors.(2) At the current pace of research it may not be long before these synthetic primordial “cells” could be working in our bodies to deliver drugs or to act as synthetic muscles cells.


1. Walde P. Building artificial cells and protocell models: Experimental approaches with lipid vesicles [Internet]. Vol. 32, BioEssays. John Wiley & Sons, Ltd; 2010 [cited 2020 Aug 18]. p. 296–303. Available from:

2. Li M, Huang X, Tang TYD, Mann S. Synthetic cellularity based on non-lipid micro-compartments and protocell models. Vol. 22, Current Opinion in Chemical Biology. Elsevier Ltd; 2014. p. 1–11.

3. Li M, Green DC, Anderson JLR, Binks BP, Mann S. In vitro gene expression and enzyme catalysis in bio-inorganic protocells. Chem Sci [Internet]. 2011 Sep 8 [cited 2020 Aug 19];2(9):1739–45. Available from:

4. Wang C, Liu H, Gao Q, Liu X, Tong Z. Facile Fabrication of Hybrid Colloidosomes with Alginate Gel Cores and Shells of Porous CaCO3 Microparticles. ChemPhysChem [Internet]. 2007 Jun 4 [cited 2020 Aug 19];8(8):1157–60. Available from:

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6. Li M, Harbron RL, Weaver JVM, Binks BP, Mann S. Membrane-gated permeability in self-activated inorganic protocells.

7. Li M, Huang X, Mann S. Spontaneous Growth and Division in Self-Reproducing Inorganic Colloidosomes. Small [Internet]. 2014 Aug 27 [cited 2020 Aug 19];10(16):3291–8. Available from:

8. Huang X, Li M, Green DC, Williams DS, Patil AJ, Mann S. Interfacial assembly of protein-polymer nano-conjugates into stimulus-responsive biomimetic protocells. Nat Commun [Internet]. 2013 Jul 30 [cited 2020 Aug 19];4(1):1–9. Available from:

9. Huang X, Patil AJ, Li M, Mann S. Design and construction of higher-order structure and function in proteinosome-based protocells. J Am Chem Soc [Internet]. 2014 Jun 25 [cited 2020 Aug 19];136(25):9225–34. Available from:

10. Kumar M, Grzelakowski M, Zilles J, Clark M, Meier W. Highly permeable polymeric membranes based on the incorporation of the functional water channel protein Aquaporin Z. Proc Natl Acad Sci U S A [Internet]. 2007 Dec 26 [cited 2020 Aug 19];104(52):20719–24. Available from: www.pnas.orgcgidoi10.1073pnas.0708762104

11. Kim KT, Cornelissen JJLM, Nolte RJM, Van Hest JCM. A polymersome nanoreactor with controllable permeability induced by stimuli-responsive block copolymers. Adv Mater [Internet]. 2009 Jul 20 [cited 2020 Aug 19];21(27):2787–91. Available from:

12. Peters RJRW, Marguet M, Marais S, Fraaije MW, van Hest JCM, Lecommandoux S. Cascade Reactions in Multicompartmentalized Polymersomes. Angew Chemie [Internet]. 2014 Jan 3 [cited 2020 Aug 19];126(1):150–4. Available from:

13. Tang TYD, Antognozzi M, Vicary JA, Perriman AW, Mann S. Small-molecule uptake in membrane-free peptide/nucleotide protocells. Soft Matter [Internet]. 2013 Aug 21 [cited 2020 Aug 22];9(31):7647–56. Available from:

14. Williams DS, Patil AJ, Mann S. Spontaneous Structuration in Coacervate-Based Protocells by Polyoxometalate-Mediated Membrane Assembly. Small [Internet]. 2014 May 14 [cited 2020 Aug 22];10(9):1830–40. Available from:

15. Rodríguez-Arco L, Li M, Mann S. Phagocytosis-inspired behaviour in synthetic protocell communities of compartmentalized colloidal objects. Nat Mater [Internet]. 2017 Aug 1 [cited 2020 Aug 22];16(8):857–63. Available from:

16. Gobbo P, Patil AJ, Li M, Harniman R, Briscoe WH, Mann S. Programmed assembly of synthetic protocells into thermoresponsive prototissues. Nat Mater [Internet]. 2018 Dec 1 [cited 2020 Aug 22];17(12):1145–53. Available from:

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