The Rise of the Nested Multicompartment Model in Synthetic Cell Research

The attractiveness of the “bottom-up” approach as a viable route for constructing cell-like systems (Luisi, 2002; Stano, 2019) is clearly evident by the ever increasing number of international projects and initiatives dedicated to this fascinating research (Supplementary Text S1). Such cell-like systems, simply called “synthetic cells” (SCs), “artificial cells” or “protocells” (although with slighly different nuances of meaning) are compartment-based systems (often, but not only, liposomes), capable of mimicking some aspects of cell behavior in a range of manners, and can be variously conceived in terms of materials, designs, and scopes. Even if current SCs are not alive, there is a recognized optimism among practicioners about the contribution of this research to basic and applied science, and there is the bet it will become one of the most important biotechnologies in the near future,—not resembling anything existing before—for example in nanomedicine (Leduc et al., 2007; Krinsky et al., 2018, Ding et al., 2018; Lussier et al., 2021). It seems a useful remark, just after mentioning nanomedicine, recalling that RNA-based anti-COVID vaccines—which actually are RNA-loaded lipid nanoparticles (Pilkington et al., 2021) have been actually developed thanks to decades of research on liposomes and other nanovectors. This suggests a highly relevant and pioneer role that current SC research might have on future ‘smart’ nanomedicine scenarios. SC research is now well recognized within the “bottom-up” or “in vitro” or “cell-free” or “chemical” domains of synthetic biology. Pioneer research, however, dates back to the early 1990s, mainly referred to the construction of protocellular models of minimal complexity for origins-of-life studies (Walde et al., 1994; Oberholzer et al., 1995; Szostak et al., 2001). In that context a minimalist design is generally applied, which means the use of allegedly primitive materials (e.g., fatty acids, ribozymes, short peptides) (Chen et al., 2005), simple architectures (single, individual compartments), and essential functions (e.g., growth-division driven by basic physico-chemical events). Relevance is given to the verification of capabilities, constraints, and properties which might have ruled the primitive life-like dynamics of compartmentalized chemical systems. On the other hand, SC research has gradually expanded and has incorporated other approaches that enriched and favored its development. In particular, current studies include systems made of various materials, mainly modern biomacromolecules (following, then, a reconstitution philosophy), but also artificial ones (e.g., block copolymers, ad hoc designed reactive surfactants (Kurihara et al., 2011; Budin and Devaraj, 2012), etc.), and their various combinations, including allegedly primitive materials (Figure 1A). Solute-filled liposomes are largely—but not uniquely—employed for that scope. Indeed, the experimental approaches are inspired by the functional (and relational (Rosen, 1991)) roles of SC components rather than their material embodiment. In a sense, SCs are tools for investigating life as it was, as it is, and as it could be. Edited by: Malcolm Buckle, UMR8113 Laboratoire de biologie et pharmacologie appliquée (LBPA), France