At first glance, cancer and viral infections have nothing in common – and, indeed, the differences run deep. However, from a treatment point of view, knowledge about both families of diseases can be exploited to develop alternative therapies. This is because both present several targets (either because they are present in an overexpressed form on the surface of neoplastic cells, in host cell receptors specific to viruses, or because they have specific target proteins for both diseases). A wide range of upregulated molecular targets (transmembrane proteins) on the surface of neoplastic cells, surrounding stroma, and tumor endothelium have been characterized for tumor cells (Sergeeva, Kolonin, Molldrem, Pasqualini, & Arap, 2006). These receptors could be explored and used in cancer treatment because this disease is the second leading cause of death worldwide (Tran et al., 2022), with approximately 10 million deaths in 2020 alone (Sung et al., 2021).

Another global public health problem is infections caused by viruses. In 2019, the world witnessed a pandemic caused by coronavirus disease (COVID-19), which is provoked by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) (Bakhiet & Taurin, 2021; Kirtipal, Bharadwaj, & Kang, 2020). The human immunodeficiency virus (HIV), responsible for the acquired immunodeficiency syndrome (AIDS), is another important virus with global impacts. The syndrome continues to kill hundreds of thousands per year worldwide, although there has been a decrease in the number of deaths related to HIV (Frank et al., 2019; Ghosn, Taiwo, Seedat, Autran, & Katlama, 2018). Arbovirus, diseases transmitted by hematophagous arthropod bite (Higuera & Ramírez, 2019), such as dengue (DENV), chikungunya (CHIKV) and zika (ZIKV), have been widely studied in recent years due to their global dissemination and epidemiological impacts (Jones et al., 2020), resulting in increased rates of morbidity and mortality (Mercado-Reyes et al., 2019). Every year, approximately 390 million people worldwide are infected with dengue (Kutsuna, Saito, & Ohmagari, 2020). Although the number of deaths is lower when compared to cancer, arboviruses are responsible for a greater number of comorbidities that can last for weeks or even years (Burt et al., 2017). A critical step in the infectious process of viruses involves both recognition and interactions with receptors exposed on the target cell membrane since these receptors play fundamental roles in viral pathogenesis, tissue tropism, and host range (Maginnis, 2018).

Blocking disease-related markers present on cell surfaces (both cancer cells and/or healthy cells), on viruses, as well as other key proteins, can be considered a crucial step for the development of new therapeutic approaches, such as in vitro display technologies (Sergeeva et al., 2006). Such approaches involve three main steps for the display and selection of bioinspired peptides: (i) the production of a library (a collection of variants to be tested); (ii) biopanning, which consists of several rounds of enrichment of variants that bind to the desired target (genotype-phenotype linkage); and (iii) the functional screening and characterization of selected variants using appropriate assays (Galán et al., 2016). Currently, there are several types of display technologies, such as virus/phage display (Guliy, Evstigneeva, & Dykman, 2023; Jaroszewicz, Morcinek-Orłowska, Pierzynowska, Gaffke, & Wȩgrzyn, 2022; Ledsgaard et al., 2022; K. Zhang, Tang, Chen, & Liu, 2022), (bacterial, yeast, and mammalian) cell surface display (Huang et al., 2020; Shibasaki & Ueda, 2023; Wang et al., 2021), enzyme surface display (Davenport & Hallam, 2022), and in vitro display technologies (Ribosomes, mRNA and covalent DNA display) (Sergeeva et al., 2006).

When compared to other display techniques, mRNA display is more advantageous because it provides a powerful means for the selection of proteins and peptides through an effective “reverse translation” (Kamalinia et al., 2020; H. Wang & Liu, 2011). Although both ribosome display and mRNA display can interrogate very large libraries of peptide variants, the advantage of mRNA display is that the mRNA itself is covalently linked to the peptide, facilitating the selection process, rather than using a ribosome to connect the mRNA and its peptide in a noncovalent ternary complex (Blanco, Verbanic, Seelig, & Chen, 2020). Additionally, when compared to phage display, mRNA display (and its variants such as transcription-translation coupled to puromycin ligand association (TRAP)), which do not require bacterial transformation, produce libraries on the order of 1012–1013 diversity, which is somewhat higher than phage display (109–1011) (Umemoto, Kondo, Fujino, Hayashi, & Murakami, 2023).

mRNA display is a useful technique for developing new therapies against cancer, as well as viral infections. Regarding antitumor treatments, mRNA display can be employed to refine peptides to bind more specifically to important targets (Shiheido, Takashima, Doi, & Yanagawa, 2011). Obviously, mRNA display is widely explored for the development of new peptides with activity against neoplastic lineages through interaction with specific molecular targets (Yang et al., 2015). Through several rounds of enrichment using a 10-amino acid mRNA display library, the H10 peptide was generated. This peptide binds to Anterior Gradient 2 (AGR2), a protein whose level of extracellular (eAGR2) increases, provoking a poor prognosis in cancer patients (Garri et al., 2018). Another example of using mRNA display for the production of new antitumor peptides is the signal peptide-based affinity matured ligand (SPAM) peptide, an 18-residue linear peptide that is nonhomologous to known programmed death ligand 1 (PD-L1). PD-L1 is a pivotal immune checkpoint ligand that provides an escape mechanism from immune surveillance when overexpressed in the cells (Kamalinia et al., 2020).

Regarding the use of mRNA display for the treatment or inhibition of viral infection, studies focus on specific proteins on the viral surface (Tanaka et al., 2022). Furthermore, it is possible to combine the mRNA display technique with others, such as high-throughput sequencing (mRNA-HST), to identify peptide mimotopes that play a crucial role in neutralizing monoclonal antibodies (mAb) (Guo et al., 2015). Another advantage of using this technique is the possibility of examine protein-protein interactions (PPIs). By utilizing the mRNA display method with a uniform distribution library (md-LED), researchers were able to gain insight into the interactions of the influenza virus NS1 protein (Du et al., 2020). Consequently, in addition to selecting specific peptides for important targets, mRNA display enables the study of PPIs, which can be further explored to construct protein-protein interaction networks in massively parallel experiments (Du et al., 2020). Throughout this review, we will address mRNA display technology for the treatment of diseases such as viral infections and several types of cancer, targeting important receptors and membrane proteins, both in the process of carcinogenesis and in the process of virus entry into host cells, as well as other proteins related to diseases.