Virus-First Theory Revisited: Bridging RNP-World and Cellular Life

Abstract

The virus-first theory presents a model in which viral lineages emerged before cells. This proposal aims to give the theory greater relevance by offering a plausible evolutionary framework that explains both (i) the origin of viruses from prebiotic chemistry and (ii) how viruses contributed to the emergence of cells. Here, we propose that viruses should be understood as a distinct class of ribonucleoprotein (RNP) systems, some of which evolved directly from the RNP-world. In our model, simple progenotes produced capsid-like particles through the evolution of a single gene encoding a self-assembling peptide. This allowed the formation of icosahedral shells around RNA genomes, as observed today in certain viral families whose capsids consist of ~60 identical subunits derived from a single gene product. These early capsids enabled mobility and protection, representing key intermediates toward biological complexity. Over time, some of those populations acquired additional peptides and evolved more elaborate architectures. Finally, the incorporation of lipid-binding domains in those capsid-like peptides allowed the formation of proteolipidic membranes akin to those found in modern cells. This model provides a gradualistic and logically coherent evolutionary path from the RNP-world to the emergence of cellular life, emphasizing the foundational role of viruses in early evolution.

1. Introduction

The virus-first theory proposes that viruses predate cellular life, emerging as self-replicating genetic elements in the early Earth. This concept can be traced back to early 20th-century thinkers such as Leonard Troland and H.J. Muller, who suggested that primitive “genetic enzymes” might represent the earliest forms of life [1] Later, one of the founders of the modern synthesis, J.B.S. Haldane, speculated that life passed through a “virus stage” before the emergence of cells [2,3].

Although viruses have long been regarded as obligate intracellular parasites—therefore, biologically dependent and unlikely to precede cellular life [4]—recent advances in virology and evolutionary theory challenge this view [5]. Viruses are increasingly seen not as degenerate cells but as evolutionarily stable strategies of life [6]. De Farias et al. [7] proposed that viruses do not require cells for replication; in evolutionary terms, they need access to a protein synthesis machinery capable of translating their proteins. Recently, it was proposed that the protoribosomes were likely present within ribonucleoprotein (RNP) condensates in the prebiotic soup, providing the infrastructure for replicating progenotes and early viral particles [8].

This perspective reframes viruses not as parasites, but as integral evolutionary agents, central to the origin and diversification of life. The concept of “dark viral matter”—the largely uncharacterized virosphere—supports the idea that viruses are the most abundant biological entities on Earth, with profound ecological and evolutionary impact [9,10,11]. Viruses modulate microbial community structure, drive horizontal gene transfer, contribute to nutrient cycling, and influence the emergence of key cellular innovations, such as the eukaryotic nucleus [12] and the mammalian placenta through the domestication of endogenous retroviruses [13,14].

Moreover, the discovery of giant viruses, such as Mimivirus, Pandoravirus, and Tupanvirus, which harbor large genomes and even translation-associated genes, has blurred the boundaries between viruses and cells, lending support to the view that viral architecture has deep evolutionary roots [15,16,17]. Even the ICTV’s concept of the virocell—which emphasizes the metabolically active phase of viruses inside host cells—indirectly acknowledges the central role of viruses in cellular evolution [18]. However, this model retains a host-centric perspective, interpreting viruses mainly as infection agents [19].

In contrast, we aim to propose a broader and more fundamental narrative: that viruses, particularly in the form of RNP-based particles, are direct descendants of the RNP-world [20]. In this framework, viruses are not peripheral anomalies but core evolutionary agents that link prebiotic RNP condensates [8] to the emergence of cellular life. Our goal in this study is to offer a theoretical model connecting the origin of viruses to the RNP-world theory [21,22], to the evolution of progenotes [23], and ultimately to the formation of cellular architecture [8].

To contextualize our proposal, we present a brief comparison of three alternative hypotheses to the virus-first model. Our aim is to demonstrate that, while the virus-first perspective has limitations, they are relatively minor when weighed against its strong explanatory power in accounting for the origin of biological compartmentalization and the evolutionary transition from viral forms to cellular life.

(i)

The RNA World theory suggests that life began with self-replicating RNA molecules capable of both storing genetic information and catalyzing biochemical reactions [24,25]. Although widely accepted and needed also in the current model, this proposal struggles to explain how metabolism emerged from RNA alone [26], another piece of evidence for an early mutualism between peptides and nucleic acids [27]. Very few examples of ribozymes with functions comparable to modern proteins have been discovered, even after extensive efforts using in vitro selection and directed evolution. While some ribozymes can catalyze specific reactions—such as RNA cleavage, ligation, and even limited peptide bond formation—their efficiency, structural versatility, and substrate range are markedly inferior to that of protein enzymes Matera [24,28,29,30]. This limitation has raised skepticism about the plausibility of a purely RNA-based early biochemistry and supports the idea that early ribonucleoprotein complexes provided more functional diversity and stability.

(ii)

The metabolism-first view proposes that life originated from self-organizing geochemical systems—such as autocatalytic cycles and proton gradients in hydrothermal vent environments—prior to the emergence of informational macromolecules like RNA and DNA. Although also important and effective, this model alone does not account for the origin of heredity, nor does it provide a detailed mechanism for the emergence of genetic encoding or the function of nucleic acids in life. For this reason, many contemporary researchers have sought to integrate metabolism-first scenarios with the RNA World theory under a framework of chemical symbiosis between metabolic networks and informational molecules [31,32].

(iii)

The virocell concept, as proposed by Forterre, views viruses as genetic parasites that evolved along with cellular life, influencing evolution through genetic innovation and horizontal gene transfer [18]. While compelling, this model assumes the prior existence of cells and does not explain the gradual evolution of complexity in living systems.

In contrast, the current approach on the virus-first model posits that capsid-forming RNP complexes have preceded cellular forms, offering structural protection, evolutionary scaffolding, and molecular packaging that later gave rise to membrane-bound cellular systems [5,8,33]. This model integrates insights from virology, structural biology, and prebiotic chemistry to provide a unifying view of early biological evolution.

Table 1. Comparative analysis of key theoretical models on the origin of life and biological compartmentalization.

Model	Main Tenets	Strengths	Limitations
Virus-First Revisited	Virus-like RNPs predate cells and contributed to the emergence of cellular life via simple encapsulation, achieving molecular protection	Proposes a role for proteinaceous compartments in pre-cellular evolution; explains capsid evolution into cells.	Lacks direct experimental evidence; difficulty in explaining host-independent replication in progenotes
RNA World	Life began with self-replicating RNA molecules that served as both information and catalyst	Supported by ribozyme activity; explains the flux of molecular information	Limited stability of RNA; unclear how membranes, metabolism, and translation evolved from RNA alone.
Virocell Concept	Viruses and cells co-evolved; viruses are metabolic parasites of host cells but play evolutionary roles.	Explains the complexity and integration of viral functions within cells; accounts for virus-cell genetic exchange	Assumes existence of fully formed cells; not a true abiogenesis theory but a model of host–virus interaction
Metabolism-First	Life began with autocatalytic cycles and geochemical gradients before information-bearing molecules evolved	Offers plausible geochemical scenarios (e.g., hydrothermal vents); can occur in mineral-rich environments.	Lacks a clear mechanism for the emergence of heredity and evolution; does not explain genetic information flow.

resumes the comparison among the models.

2. A Current View of the RNP-World

The ribonucleoprotein (RNP) world theory proposes that the earliest biological systems that allowed the emergence of the life phenomenon were assemblies of RNAs and peptides [21,22,34]. According to this model, while the RNAs played a central role in the early development of biological systems due to their informational and catalytic capacities under the RNA-world perspective, it is unlikely that they would have achieved the complexity required for life in the absence of a symbiosis with peptides [31]. Peptides are much more versatile molecules, built as a chain of amino acids that are very different in their chemical and physical characteristics. This structural versatility makes peptide polymers capable of interacting with and binding other molecules in the primitive soup more efficiently than nucleic acids. Together, a world of ribonucleoproteins offers a remarkable explanatory power: while the RNAs maintain their role in storing information, the molecular evolutionary processes ended by selecting peptides as the most important molecules for molecular binding and catalysis [35]. This limited catalytic capacity of RNAs is a strong criticism of the idea that enzymes from basal metabolism were once ribozymes that have been further substituted by amino acid polymers, as proposed by some RNA-world advocates. The combined properties of nucleic acids and peptides make RNP complexes the strongest drivers of molecular evolution on the prebiotic Earth [36].

In this theoretical scenario, the biological system referred to as the First Universal Common Ancestor (FUCA) originated as an RNP-based system, on which basic translation mechanisms and a primitive form of the genetic code first arose [37,38]. Along the maturation of the genetic code, nearly random peptides functioned as constituents of RNP aggregates. FUCA represents the conceptual link between the RNA world and the peptide-rich metabolic networks theorized in hypercycle models [39,40,41,42]. While creating a biological code of information displacement between chemical polymers (i.e., the genetic code), FUCA populations allowed the emergence of the first peptide-coding genes: stretches of RNA that organized the order and quality of amino acids in a peptide. It is within this interface that the concept of chemical symbiosis takes shape: RNAs and peptides co-evolved in a mutually beneficial interaction that incrementally increased molecular complexity [27,31,43].

As this symbiosis progressed, peptides began to contribute to RNA stability and functional expansion, and RNP systems emerged as central players in the early molecular repertoire of life [23].

Then, the most successful FUCA populations gave rise to more sophisticated RNP-based systems named progenotes: dynamic and membraneless RNP structures [7,44]. Some of those progenotes’ main roles were acting as coacervates, providing protected aqueous microenvironments (prebiotic refugia) that facilitated chemical reactions [45,46,47]. With time, progenotes RNA-based genomes grew and developed increasingly elaborate genes capable of encoding more effective peptides [48], which in turn facilitated the emergence of rudimentary metabolic circuits. This progression reinforces the theory that RNPs were the first supramolecular systems capable of orchestrating vital biochemical functions, including information replication, enzymatic activity, and primitive metabolism [23]. Those populations of progenotes grew by mutation and by concatenation and mixing of their informational content. Together, molecular natural selection favored the progenote populations capable of encoding peptides that bound to molecules in the prebiotic soup and accelerated their cycling [49]. Little by little, spontaneous molecular cycles already happening in the milieu [41,42] were incorporated into biology as randomly formed peptides happened to bind some of these molecules and accelerate their transformation. Any encoded peptide capable of binding nucleotides and amino acids to facilitate and increase their production would be favored in that context. A strong piece of evidence supporting this view comes from the evolutionary history of ribosomes. Several authors suggest that the ribosome, an RNP complex, emerged very early in the history of life on our planet, possibly being the first structure to become established in forming biological systems [50,51,52]

Thus, the route of complexification was in course, and different populations of progenotes possibly maturated different biochemical pathways until reaching about 300 specific genes and allowing the emergence of cellular life under the perspective of a Last Universal Common Ancestor (LUCA) [53,54].

Although this symbiotic view may seem new, its roots can be traced back to pioneering insights from H.J. Muller, who speculated in 1929 that life might have originated through “genes” acting as autocatalytic entities even before the rise of cells [55]. For some, his reflections anticipated the idea that primitive systems based on nucleic acids and peptides could have encoded and catalyzed life-like processes long before the emergence of complete cells. Such visionary thoughts align remarkably with modern formulations of the RNP-world, where ribonucleoprotein assemblies are posited as the earliest organized biological units. This perspective further underscores the conceptual continuity between early theoretical models and contemporary molecular evidence, reinforcing the plausibility of a joint RNA–peptide origin for biological systems [32].

3. The Emergence of Compartmentalization

We need to go back in time a little to understand how those progenotes could exist without any sort of membrane. At the molecular scale, it has been warmly discussed in the literature that pre-cellular forms of compartmentalization could be acquired by some sort of liquid–liquid phase separation (LLPS) [8,56,57,58,59]. LLPS are known as agglomerates formed mainly by RNP particles that provide some sort of compartmentalization inside cells, creating aggregates of organic molecules in aqueous substrates. Those protocompartments were primarily composed of intrinsically disordered peptides bound to RNAs, which formed dynamic, multivalent interactions capable of constituting flexible and responsive biomolecular condensates [8,60,61,62,63]. Current RNA-binding proteins such as FUS, TDP-43, and hnRNPA1 exemplify this behavior, assembling reversible, phase-separated structures crucial for intracellular organization [45,64]. In early evolution, similar interactions between RNAs and disordered peptides likely enabled the spontaneous formation of protocondensates under prebiotic conditions, offering a membraneless route to molecular compartmentalization [45,46,65].

Beyond their structural roles, coacervates may have played a functional role in the origin of coding mechanisms. As proposed in recent studies [8], the dynamic nature of liquid–liquid phase-separated compartments—formed from intrinsically disordered peptides and RNAs—could have promoted the co-localization of essential prebiotic components such as ribozymes, proto-tRNAs, and aminoacylating peptides. This spatial proximity would have enhanced the emergence of early coding rules, favoring interactions between specific RNA sequences and amino acid residues. In such environments, peptide-RNA symbioses likely advanced through cycles of selective stabilization and feedback, reinforcing functional assemblies. Recent theoretical and experimental models also suggest that coacervates can increase the local concentration of molecules involved in translation-like processes, including tRNA mimics and ribozymes with peptide bond-forming capacity [65,66]. Consequently, the coevolution of compartmentalization and coding might not have been coincidental but interdependent. This view is consistent with the chemical symbiosis model, where RNA and peptides reciprocally enhanced each other’s evolutionary potential, driving the system toward higher levels of molecular organization and ultimately paving the way for translation-capable progenotes.

4. The Emergence of Viruses from Progenotes

The initial level of compartmentalization in biological systems therefore involved LLPS-like systems operating by RNPs within the primordial soup, effectively sequestering nucleic acids and their building blocks, together with other ions and inorganic molecules necessary for primitive metabolism. Once this first level of aqueous separation by LLPS-based coacervates was stable and well-established, the inherent process of modification by mutation and selection continued to happen. To understand the next stage along the evolution of biological compartmentalization, we must search for the simplest form of compartments found today in biological systems. Membranes are highly complex structures made of long hydrocarbon chains (lipids), a sort of molecule that is still poorly related to the RNPs that sparked the life phenomenon [22]. If we aim to praise logic and coherence, we need to look for some encapsulation mechanism made only by peptides or RNPs.

Recent progress in in vitro systems and computational modeling has provided encouraging results that support the plausibility of the transition from LLPS-like compartments to capsid structures. For example, self-assembling peptides and RNA have been shown to form phase-separated condensates through liquid–liquid phase separation (LLPS), which can serve as functional, membrane-less compartments [67,68]. Additionally, simulations and experimental models demonstrate that these condensates can adopt organized, shell-like architectures, suggesting a potential pathway for the emergence of capsid-like enclosures [69]. While these systems do not yet replicate early Earth conditions, they offer promising avenues for experimental validation of the transitions from RNP condensates to primitive capsids.

4.1. The Simplest Form of Biological Encapsulation: Single-Protein Capsids

The simplest forms of biological encapsulation known today are found in some viral families that adopt T = 1 icosahedral symmetry, such as those from the satellite virus group and Circoviridae. These viruses are capable of producing capsids composed of slight variations in a protein encoded by a single gene product. Satellite Tobacco Mosaic Virus (STMV) and Porcine Circovirus (PCV) are well-studied examples of viruses that assemble their capsids from 60 identical subunits to form compact, highly stable structures.

STMV is a small, single-stranded RNA virus that requires co-infection with Tobacco Mosaic Virus (TMV) for replication. Its capsid is ~17 nm in diameter and composed of 60 capsid proteins arranged in a T = 1 icosahedral lattice. Each subunit adopts a jellyroll β-barrel fold, where two β-sheets of antiparallel strands are packed into a sandwich-like configuration. These subunits interact tightly through hydrophobic and electrostatic interfaces, forming a highly symmetric shell with limited internal volume—just enough to encapsulate its ~1.1 kb genome [70]. The RNA interacts with the capsid proteins via conserved stem-loop structures that guide the assembly process. Many other satellite viruses follow similar strategies, including Satellite Tobacco Necrosis Virus (STNV), Satellite Panicum Mosaic Virus (SPMV), and even animal-associated Adeno-Associated Virus (AAV), all of which require helper viruses for replication [71]. Importantly, no autonomous satellite viruses have been described so far; all known examples depend on co-infection to complete their life cycles.

Porcine circovirus (PCV), a member of the Circoviridae family, is one of the smallest known animal DNA viruses. It possesses a circular single-stranded DNA genome of approximately 1.7 kb and a capsid of ~17 nm, also built from 60 subunits arranged with T = 1 symmetry. The PCV capsid protein (Cap) similarly adopts a jellyroll fold, forming a structurally rigid shell stabilized by calcium ions and internal interactions among the N-terminal arms of neighboring subunits [72]. The Circoviridae family includes several members such as PCV1, PCV2, PCV3, and PCV4, as well as Beak and Feather Disease Virus (BFDV) and Canine Circovirus, but all known members possess ssDNA genomes, and no RNA-based circoviruses have been reported [73,74].

Although these two families above likely represent more derived viruses—since one requires co-infection and the other uses DNA—there are also slightly more complex capsid assemblies that deserve attention. Viruses with icosahedral symmetry—such as those from Leviviridae, Tombusviridae, and Nodaviridae—assemble capsids from 180 copies of the capsid protein, allowing for larger internal volumes and more complex packaging strategies. In both T = 1 and T = 3 geometries, some capsid assemblies are aided by the presence of divalent ions, such as Ca²⁺ or Mg²⁺, which stabilize protein–RNA and protein–protein interactions and could plausibly have been available in the primordial soup [75]. These simple yet effective self-assembling viral architectures represent plausible models for early molecular compartmentalization, creating sophisticated microenvironments capable of encapsulating and protecting the viral chromatin while requiring minimal molecular complexity.

In the Leviviridae family, the bacteriophage MS2′s capsid is constructed from 180 copies of a single capsid protein (CP) with a size of 14 kDa. These proteins arrange into an icosahedral structure with T = 3 symmetry, forming 60 quasi-symmetric AB-dimers and 30 symmetric CC′-dimers. The A and C subunits are positioned around the three-fold axes, while the B subunits are located around the five-fold axes of the icosahedron. The CPs exhibit a unique fold distinct from the classic jellyroll motif observed in many other viral capsid proteins. During assembly, specific RNA sequences interact with CP dimers, facilitating the precise formation and stabilization of the capsid structure [76].

In the Tombusviridae family, viruses such as the Tomato bushy stunt virus have capsids with approximately 32–35 nm in diameter, consisting of 180 identical CP subunits. These subunits also adopt the three conformational states labeled A, B, and C, achieving a T = 3 icosahedral symmetry. Each CP subunit features a jellyroll β-barrel structure, comprising two antiparallel β-sheets that create a stable, compact fold. The assembly involves intricate protein–protein interactions, where the N-terminal regions of the CPs contribute to the formation of the inner surface of the capsid, while the C-terminal regions participate in external contacts, ensuring structural integrity.

Within the Nodaviridae family, exemplified by the Black beetle virus, the capsid is also formed by 180 copies of the capsid protein alpha, which self-assemble into an icosahedral procapsid measuring about 30 nm in diameter. Again, each capsid protein adopts a core jellyroll topology, forming a face-to-face β-sandwich with two pairs of antiparallel β-sheets. During assembly, the capsid protein alpha undergoes a self-catalyzed cleavage, resulting in proteins beta and gamma, which are essential for the structural maturation of the capsid. This cleavage facilitates the stabilization of the capsid structure and is crucial for the infectivity of the virus [77].

Such assembly of viral capsids from 180 similar protein subunits into an icosahedral structure follows well-defined geometric and structural principles [78]. Although an initial assumption might suggest that each of the 20 triangular faces is formed by exactly 9 proteins, this is not how the structure assembles. Instead, each face contributes with parts of different hexamers and pentamers, leading to the seamless icosahedral arrangement. Each triangular facet is a shared region where adjacent hexamers and pentamers interlock, forming a continuous network across the entire capsid. In the T = 3 icosahedral symmetry, the 180 proteins are arranged in 60 asymmetric units, each containing those three subunits in different conformations (often labeled as A, B, and C). These proteins do not simply form 9-membered clusters on each triangular face but rather arrange into pentamers and hexamers that tessellate across the capsid surface to ensure a robust and energy-efficient assembly. Each triangular face of the icosahedron contains a mix of hexameric and pentameric clusters of proteins. The 12 vertices of the icosahedron are occupied by pentamers, each composed of 5 capsid proteins, while the triangular faces between them contain hexamers, each consisting of 6 proteins. Because an icosahedron has 12 vertices and 20 faces, the proteins distribute as follows: (i) 12 pentamers: 12 × 5 = 60 proteins and (ii) 20 hexamers: 20 × 6 = 120 proteins, totaling 180 proteins. Each protein subunit is folded into a jellyroll β-barrel structure, which allows for stable lateral contact with neighboring proteins. The A, B, and C conformers exhibit slight variations in their orientation, allowing them to interact flexibly within hexameric and pentameric arrangements. The N-terminal arms of the proteins often engage in electrostatic or hydrophobic interactions, stabilizing the pentameric and hexameric contacts. Figure 1 summarizes the current proposal. Additionally, some viruses encode auxiliary scaffolding proteins that temporarily guide this self-assembly, ensuring the proper curvature and spacing.

In summary, these viral families employ a highly efficient strategy in which multiple copies of a single capsid protein self-assemble into an icosahedral structure, achieving maximal stability with minimal genetic and energetic investment. Although seemingly intricate, this architecture represents the simplest known encapsulating system in biological systems, relying on fundamental principles of symmetry, self-organization, and cooperative protein–protein interactions [78]. The specific folding patterns and binding interfaces of these capsid proteins are crucial not only for structural integrity but also for the encapsulation and protection of nucleic acids, a feature that could have provided a significant evolutionary advantage in prebiotic systems. Also, it is known that viruses presenting icosahedral capsids and membranes can infect hosts from all life domains [79].

Additionally, we must acknowledge that viruses infecting archaea also exhibit pseudoicosahedral capsids and might provide examples of simple encapsulation systems. Members of the Sulfolobus spindle-shaped virus family, while non-icosahedral in morphology, encode capsid proteins homologous to the single jelly-roll (SJR) fold found in many icosahedral viruses [80]. Furthermore, archaeal viruses such as Sulfolobus turreted icosahedral virus (STIV) adopt T = 3 capsids built from a double β-barrel fold, considered homologous to the SJR fold found in bacterial and eukaryotic viruses [72]. These examples underscore that pseudoicosahedral or icosahedral architectures were also present in viruses infecting the archaeal domain, reinforcing the hypothesis that such structural strategies may have evolved prior to the divergence of the primary domains of life.

4.2. Simplicity and Connection with RNP-World Ideas

Considering the minimalistic yet highly effective nature of these viral capsids, we propose that similar self-assembling protein structures could have played a pivotal role in the early stages of biological evolution. In a pre-cellular world, capsid-like protein assemblies functioned as primordial protective enclosures for the genetic material, shielding them from degradation while facilitating molecular interactions necessary for early replication and metabolic-like processes [81,82]. An intriguing question would be why those forms of encapsulation did not acquire the ancestral ribosomes into them. It is plausible that the structural and physicochemical constraints of peptide-based capsids were incompatible with the spatial and functional requirements of ribosomes, possibly due to limited internal volume or the absence of a conducive microenvironment for translation. Although we cannot yet answer this question, this is the reason why cells were so highly successful when they emerged, as they could also contain those highly relevant complexes for peptide synthesis. In any case, the origin of capsids made of single peptides highlights Haldane’s idea that viruses or virus-like systems were central to the evolution of life, providing early forms of genetic exchange and mobility across diverse microenvironments [5].

Additionally, the self-assembly properties of icosahedral capsids suggest that such structures could have spontaneously emerged under prebiotic conditions, driven by similar thermodynamic and kinetic principles that govern modern viral assembly [69]. The presence of symmetrical capsids in extant viruses across all domains of life further supports the notion that this strategy is deeply rooted in evolutionary history, potentially preceding cells [33,83]. In this context, viruses emerged as part of the community of progenotes that acquired a certain degree of compartmentalization without incorporating the translator progenotes necessary for the synthesis of their proteins. The absence of a protoribosome and the limited autonomy of those systems must have established selective pressure for the maintenance of intense interaction with other constituents of the progenote community. From this interaction, the relationship between viruses and cells may have emerged [7].

4.3. Metastable Capsids, RNA Delivery, and the Spatial Regulation of Prebiotic Replication

In the context of prebiotic evolution, it is plausible that the first protein-based capsids were not rigid, permanently stable shells, but rather metastable structures. These early capsids likely conferred selective advantages by temporarily protecting RNA genomes from chemical degradation, UV radiation, or enzymatic hydrolysis while in transit through the heterogeneous primordial environment. Such metastability would have allowed the encapsulated RNA to be spontaneously released in favorable contexts—particularly in proximity to translation-competent progenotes with rudimentary ribosomal activity (FUCA-like systems). These encapsulating proteins, therefore, functioned not only as protective enclosures but also as primitive delivery vehicles, enabling a form of early spatial regulation of replication [48,81].

By increasing the local concentration of RNA templates and catalytic partners within confined volumes, these metastable structures could have enhanced reaction kinetics and replication efficiency, even without the enzymatic sophistication of later systems [69,84]. This scenario also supports the idea that early compartmentalization was functional rather than strictly structural: capsids served a dynamic role in facilitating gene expression cycles by relocating replicators into chemically permissive niches. The evolutionary success of such a system might depend more on its efficiency in genome delivery than on long-term capsid stability—marking a crucial intermediate in the transition from progenotes to cellular life.

5. A Brief Approach of Virus to Cell Transition

Over time, some progenote populations capable of producing simple self-assembling capsids began to increase the structural and functional complexity of those coats. This occurred through the progressive incorporation of additional proteins in the capsid-like structures, some of which were co-opted to serve specific roles such as molecular channels, environmental sensors (receptors), and binding interfaces for molecules. These functional enhancements allowed virus-like particles to interact more effectively with their surroundings and to regulate the transport of molecules across their boundaries. Eventually, the emergence and recruitment of peptides containing lipid-binding domains enabled the anchoring and organization of lipid molecules on the capsid surface [8]. Emerging in some progenote populations, this interaction likely facilitated the transition from purely proteinaceous coats to hybrid proteolipidic structures, resembling modern cell membranes.

While protein capsids and lipid bilayers assemble through different physical principles—specific subunit interactions versus hydrophobic-driven self-assembly—these differences do not preclude the existence of intermediate forms. In fact, many modern proteins show evidence of such transitions. For example, the E. coli lipocalin Blc binds fatty acids and lysophospholipids using a β-barrel fold [85]. Similarly, annexins (e.g., annexin A5/A8) facilitate calcium-dependent binding to phospholipid membranes, helping to bend and organize lipid layers [86]. The widespread presence and functional versatility of these proteins today support the idea that peptide domains could have gradually enabled lipid integration into pre-existing protein shells. Furthermore, some membrane-associated viruses, like poxviruses and certain archaeal viruses, have internal capsids enveloped by lipid membranes, serving as real-world examples of proteolipidic intermediates [82].

These early proteolipidic compartments not only improved the efficiency of encapsulation and molecular retention but also laid the foundation for the emergence of protocells, providing the boundary conditions necessary for compartmentalized metabolism, signaling regulation, and replication control [87,88]. In some of these systems, the incorporation of ribosomes into their interior marked a key evolutionary turning point, granting them the capacity for autonomous protein synthesis and thereby transitioning from viral-like replicators to truly cellular forms [8]. This emergence of autonomy and vertical inheritance distinguished these ribosome-containing proteolipidic progenotes from their contemporaries—viral lineages that remained dependent on external translation systems for replication.

Contextualizing the emergence of proteolipidic membranes under the history of LUCA gives us new insights. Here, we propose that viral strategy probably emerged before the prokaryotic ancestor (LUCA) and therefore before cells. The most successful progenotes paved the way to the emergence of LUCA: the ancestor of the two basal cellular lineages [48]. It is interesting to note that, while most basal pathways show homology between archaea and bacteria, at least in their central points, both (a) DNA biosynthesis and (b) lipid biosynthesis do not. This means that a completely different set of enzymes is responsible for making either DNA or lipids in bacteria and archaea [38]. One interpretation of this fact is that those two pathways were the last ones along the evolution of life and were acquired independently by each prokaryotic group [89,90,91,92,93]. Membrane biogenesis therefore putatively arose two times in the evolution of life, when lipid-binding peptides were embedded into protein protocapsids in (i) bacteria and (ii) archaea [8]. This fact highlights a broader evolutionary trend in which metabolic innovations emerge through stepwise modifications of pre-existing protein functions, rather than abrupt, de novo invention of entirely new molecular machinery [94]. The current stepwise explanation for virus-capsid evolution and the emergence of proteolipidic membranes provides a logical, gradualistic, and coherent view to solve this molecular puzzle.

6. Discussion

While the “virus-first” theory has gained renewed attention as an alternative to cell-centered models of the origin of life, the terminology itself warrants scrutiny. The notion of “first” suggests a primacy of viruses over all other biological systems yet fails to capture the complex evolutionary continuum between prebiotic chemistry and cellular life. In the model proposed here, viruses do not precede all forms of biological systems but rather emerged as a crucial step following the formation of RNP-based progenotes and intermediating the rise of cells. These progenotes, composed of naked RNPs compartmentalized in coacervates made of their same constitution, represent a primitive form of molecular self-organization rooted in prebiotic chemistry and consistent with RNP-world scenarios [21,22]. Those progenote systems were capable of genetic encoding and translation when in symbiosis with other progenotes harboring translator systems. Thus, while we argue that viruses predate cells, being a necessary step to their emergence, it must be clear that they do not predate all biological systems. Instead, we argue that viruses emerged as a transitional strategy: encapsulated RNP systems optimized for genome protection, environmental mobility, and interaction with primitive translational machinery [8,33]. Consequently, the “virus-first” label can be misleading if interpreted literally.

Our argumentation focuses on the emergence of capsid-like structures in primordial conditions, evidencing this as a crucial step in the early transition from nearly disordered prebiotic chemistry to the structured complexity of biological systems. The widespread conservation of simple capsid structures across diverse viral lineages suggests that some of them should not be understood as molecular innovations but rather as the maintenance of ancient molecular architectures [33,82].

This perspective challenges the traditional view of viruses as cellular parasites, instead positioning them as molecular systems that rely on other ribosome-containing systems for replication [7]. In evolutionary terms, the idea that viruses are not strict cellular infectants but rather ribosome-dependent RNP systems indicates that their existence was deeply intertwined with the emergence of translation-capable biological systems [81]. In prebiotic terms, encapsulated genomes would have needed to meet progenotes containing the rudimentary translational machinery (FUCA-like) to enable their propagation, a scenario that aligns with theories proposing a co-evolutionary relationship between early genetic replicators and primitive translation systems [37].

Furthermore, the encapsulation of genetic material within proteinaceous capsids conferred significant selective advantages by promoting protection and endurance in highly fluctuating environmental conditions [69,84]. This protection increased the persistence and evolutionary potential of early capsid-containing progenotes and allowed for horizontal gene transfer between those systems [11]. Notably, the ability of capsids to transport genetic material across different microenvironments can be seen as a precursor to modern viral infection mechanisms and gene transfer strategies, reinforcing the idea that viruses also played this fundamental role in the emergence of complex biological systems [5,20,95].

The following significant step in the evolution of biological compartmentalization was the emergence of cells. While many modern viruses acquire their lipid envelopes by budding through host membranes, we propose that ancestral capsid-like structures evolved the ability to bind lipid components independently. This happened after the success of some capsid-containing progenotes in a moment in which different populations had already been in place and evolved other peptides (such as channels and receptors) capable of binding their capsids. At some point, some capsid peptides would gain lipid-binding domains, starting to recruit lipids from the milieu, eventually producing membranes. This idea is corroborated by the fact that cell membranes are not lipidic but proteolipidic [8]. The peptide parts of cellular membranes are therefore rooted in this ancient mechanism. Such proteolipidic intermediates may have predated fully cellular membranes and represent a transitional form.

To summarize this model, we provide an illustration with the proposed evolutionary trajectory from prebiotic chemistry to the emergence of virus-like particles, grounded in the RNP-world framework (Figure 2). Starting from coacervate-based systems composed of intrinsically disordered peptides and RNAs [8], the model proposes the origin of FUCA as the point where primitive genetic encoding and peptide synthesis mechanisms first emerged [37]. FUCA then diversified into distinct progenote populations, both translators and populations with distinct molecular binding abilities [49]. Some of these progenotes evolved self-assembling capsid proteins, resulting in encapsulated forms that would later give rise to virus-like entities through structural complexification. Altogether, this scenario emphasizes a modular and stepwise progression in which encapsulated RNP systems and translation machinery co-evolved in separate but interacting populations, eventually converging toward the emergence of cellular complexity.

While the virocell concept has been an important step in redefining viruses as dynamic and metabolically active entities during their intracellular phase [18], it remains conceptually anchored in a cell-first paradigm. The theory postulates that viruses acquire biological activity only within host cells, implicitly assuming that viruses arose from pre-existing cellular life. While this model effectively reframes viruses as agents of genetic innovation and ecological interactions, it does not account for their potential origins in prebiotic chemistry. In particular, it does not engage with current molecular evolution theories based on the RNP-world theory, which propose that life emerged gradually from self-organizing RNP condensates before the advent of cellular membranes [22,58]. In contrast, our model starts from a bottom-up framework, grounded in biophysics and chemical evolution. We propose that viruses, or virus-like entities, evolved as early ribosome-dependent RNP systems in a world where translation-capable progenotes already existed but lacked membranes, being compartmentalized in RNP aggregates (coacervates) [8]. At some point they have acquired a self-folding protein capable of boxing together with their copies. This molecular innovation allowed for a gradual and chemically plausible transition from progenotes to viral architecture. While we acknowledge that some modern viruses indeed evolved through reductive processes from cells—as posited by the virocell model—this scenario cannot explain the first appearance of capsid-based compartmentalization, nor does it address the origin of cellular membranes. The viral architecture is paraphyletic, and it is an evolutionarily stable strategy recurrently found by evolving biological systems. Plus, the current proposal interestingly opens a new venue in virus taxonomy in distinguishing (a) viral architectures and clades that originated straight from progenotes and (a’) the ones that originated by simplification of cellular structures. Finally, Forterre’s virocell concept can be interpreted not as a contradiction, but as a complementary model aligned with virus-first perspectives—representing a later evolutionary stage in which viral processes integrated deeply into emerging cellular systems.

Another important issue that emerged as a consequence of the long-standing relationship between viral and cellular lineages is the existence of endogenous viral elements (EVEs), such as human endogenous retroviruses (HERVs), which now constitute over 8% of the human genome. These elements are molecular fossils of ancient viral infections and provide compelling evidence for the deep integration of viral functions within cellular genomes. Their persistence and co-evolution with host genomes reinforce the plausibility that viruses were present from the earliest stages of cellular evolution, consistent with the virus-first model. However, while endogenous retroviruses are often cited as evidence of virus–host genetic integration, most of them probably represent relatively recent events in genomic evolution and are not directly informative about pre-cellular stages or the origin of viruses themselves.

In the context of the virus-first model, we should acknowledge that the emergence of non-enveloped capsids represents an ancestral form of molecular compartmentalization. These protein capsids, built from repetitive subunits, could have offered a selective advantage in stabilizing RNA in the aqueous environments of early Earth. As life evolved, lipid-binding domains may have been co-opted into these structures, giving rise to proteolipidic intermediates and eventually to membrane-enclosed compartments resembling modern enveloped viruses. However, it is important to stress that viral evolution is a continuous and highly adaptive process. Both enveloped and non-enveloped viruses continue to emerge, diversify, and evolve. The presence of structural simplicity in modern viruses should not be conflated with ancient origin. Instead, the principles of convergent evolution and functional optimization suggest that both viral forms (non-enveloped and enveloped) may independently arise in different evolutionary contexts [6].

While our model provides a coherent theoretical framework for virus-first evolution and the stepwise emergence of compartmentalization, it remains, at present, a conceptual synthesis awaiting empirical validation. Experimental reconstruction of RNP condensates, viral capsid self-assembly, and proteolipid intermediates under prebiotic-like conditions could offer valuable insights into the feasibility of the transitions proposed here. Recent advances in in vitro evolution, synthetic virology, and artificial cells make these tests increasingly plausible and may allow researchers to replicate elements of early compartmentalization in controlled settings.

The current proposal supports the idea that the first biological systems did not arise in isolation but emerged within a dynamic network of interacting molecular entities, where virus-like particles played a central role as mediators of genetic exchange and evolutionary experimentation. The existence of viral systems before the advent of membrane-bound cells helps explain the deep structural and functional relationships between viral and cellular proteins, as well as the long-term persistence of viral lineages throughout evolutionary history [96,97]. Therefore, the study of ancient viral structures not only informs our understanding of early biological organization but also challenges conventional paradigms regarding the origin of life and the role of viruses in shaping the evolutionary landscape [20].

7. Conclusions

Here, we propose that the simplest viral capsids known today—formed by 60 copies of a single gene product (T = 1)—likely emerged within a population of progenotes in the RNP-world. These self-assembling capsid structures provided early encapsulation strategies for RNP-based systems. Over evolutionary time, some of these progenote systems increased in complexity through the incorporation of additional proteins co-opted to function as channels, receptors, and molecular binders. Eventually, the integration of peptides with lipid-binding domains into some populations presenting capsid-like structures enabled the formation of proteolipidic membranes, giving rise to cell-like entities. This transition also allowed the internalization of coacervate-like cytoplasmic elements and the recruitment of translational progenotes, such as protoribosomes, into a stable cellular framework. Altogether, this study presents a coherent theoretical model that bridges the virus-first and RNP-world hypotheses while also providing a plausible pathway for the origin of cellular membranes from primitive protein-based encapsulation systems.

Therefore, throughout this manuscript, we aimed to (i) revisit and honor Haldane’s early proposal of a “virus stage” in the history of life, (ii) present a coherent and gradualist scenario that links prebiotic chemistry to the emergence of viruses and cells, and (iii) contribute meaningfully to the ongoing debate surrounding the virus-first debate.