22 May 2025
Peptides are molecules composed of two or more amino acids linked by peptide bonds, and they play essential biological roles. In recent decades, peptides have become pivotal bioactive ingredients in pharmaceuticals and cosmetics due to their unique features. Originally developed for therapeutic purposes, peptides have gained popularity in the cosmetic field, providing solutions for anti-aging, whitening, moisturizing, and skin repair. Moreover, innovations such as artificial intelligence-assisted peptide design, efficient delivery systems, and the integration of multifunctional ingredients have significantly contributed to the industry’s rapid evolution. This review explores the historical milestones of peptides in medicine and cosmetics, delves into cutting-edge synthesis technologies, and dissects the molecular mechanisms behind their cosmetic properties. Research in medicinal peptides has promoted the development of cosmetic peptides. Despite their potential, challenges such as stability, bioavailability, and cost-effective production remain barriers to widespread adoption. Future studies should focus on enhancing peptide stability, developing synergistic formulations, and conducting large-scale clinical trials to validate long-term efficacy. With continuous innovation, peptides are poised to redefine the cosmetic industry, bridging the gap between pharmaceuticals and skincare for safer and more effective solutions.
Peptides have emerged as a cornerstone in the pharmaceutical and cosmetic industries due to their high specificity, biocompatibility, and diverse biological activities. As short chains of amino acids, peptides have been widely reported to function in critical physiological processes, including signaling, repair, and regulation at the molecular level [1]. Their unique properties have made them indispensable in addressing challenges ranging from chronic disease management to enhancing skin health.
Since the 1990s when the first peptide was introduced into cosmetics [2], various natural or synthetic peptides have been utilized as active ingredients for anti-aging, whitening, and anti-inflammation, et al. [3,4,5,6]. Advances in chemical and biochemical synthesis techniques largely facilitate the industrial-scale production of peptide-based drugs and promote the integration of peptides into cosmetics [7,8,9,10,11].
As the global market for peptide-based products, including therapeutic peptides, cosmetic peptides, and nutraceuticals, continues to experience significant growth, the cosmetic peptide manufacturing market alone is projected to grow at a compound annual growth rate (CAGR) of 10.3% through 2034, with its value expected to increase from USD 3770.00 million in 2024 to USD 8259.34 million by 2032 [12]. As the peptide market for peptide-based products continues to grow, understanding their historical evolution, technological breakthroughs, and underlying biological mechanisms is crucial for advancing both research and commercial applications in this rapidly expanding field.
This review aims to explore the multifaceted world of peptides by examining their historical development, the technologies that have shaped their production and application, and the mechanisms through which they achieve their effects. By analyzing these aspects, this article provides a comprehensive understanding of peptides’ roles and potential in advancing both pharmaceuticals and cosmetics.
The evolution of peptide science spans more than a century, including both pharmaceutical and cosmetic innovations. A timeline of key milestones is illustrated in [Figure 1].
Historical timeline of major breakthroughs in peptide research and development. The timeline illustrates the evolution of peptide science from the first dipeptide synthesis in 1901 to recombinant insulin production, the advent of SPPS, phage/mRNA display technologies, and recent advances in cosmetic applications.
Peptide research can be traced back to the early 20th century [13,14,15]. In 1901, the dipeptide Gly-Gly was first synthesized by Fischer’s group [14], initiating peptide synthesis chemistry. Insulin was isolated from dog pancreas in 1921, setting the milestone of the therapeutic application of peptides in treating metabolic diseases such as diabetes [16]. After that, several peptides were identified as bioactive molecules, such as substance P, which is involved in blood pressure regulation and the induction of corticotropin in endocrine signaling [17,18]. It is worth mentioning that not until 1951 was insulin fully sequenced by Frederick Sanger [19], and bovine insulin was successfully chemically synthesized in the mid-1960s [16,20,21]. This represents the progress of peptide synthesis, thereby enabling the massive production of peptide-based drugs, shifted from natural extracts.
The advent of solid-phase peptide synthesis (SPPS) in 1963 revolutionized peptide production, marking a transformative milestone in synthetic chemistry [7,8,11]. This groundbreaking technique streamlined the assembly of peptide chains through its innovative stepwise approach on an insoluble polymer support, dramatically enhancing both synthetic efficiency and cost-effectiveness. The clinical application of SPPS-synthesized peptides reached a significant milestone in the late 1980s [7,11], as evidenced by the FDA approval of octreotide in 1988 [22]. This landmark achievement not only validated SPPS as a robust platform for pharmaceutical production but also demonstrated its unparalleled capacity for the large-scale synthesis of structurally complex, biologically active molecules with precise sequence control.
The emergence of recombinant DNA technology in the 1960s marked a new era for peptide research. A pivotal advancement occurred in 1978 with the successful production of recombinant insulin by David Goeddel and his colleagues [16,23], which demonstrated the feasibility of industrial-scale peptide manufacturing through genetic engineering techniques. This breakthrough culminated in the 1982 approval of recombinant insulin, marking the first commercially available genetically engineered peptide drug and establishing a new paradigm for therapeutic development [23,24]. The subsequent discovery of glucagon-like peptide-1 (GLP-1) in 1986 by Mojsov and colleagues further expanded peptides’ therapeutic applications, particularly in metabolic disease management [25]. Recently, the GLP-1 market has experienced rapid expansion, fueled by its applications in type 2 diabetes, obesity, cardiovascular diseases, and beyond. With global leaders like Novo Nordisk and Eli Lilly dominating the market, along with emerging players from China driving innovation in oral formulations and multi-target agonists, the GLP-1 sector is on track to become a multi-billion-dollar industry. These milestones collectively transformed peptide science from laboratory curiosities to mainstream therapeutic agents, laying the foundation for the modern biopharmaceutical industry.
Display technologies, particularly phage display, which was awarded the Nobel Prize in 2018 [26], have greatly enhanced the efficiency and simplicity of peptide screening. Phage display is a technology based on the presentation of functional exogenous peptides, enabling the selection and amplification of specific peptides in vitro, like natural selection. Through multiple rounds of screening under selective pressure, peptides with a high affinity for target proteins can be enriched and amplified, while those with weak binding are eliminated.
Both the anti-tumor necrosis factor α (anti-TNF-α) antibody Adalimumab and the anti-B lymphocyte stimulator antibody Belimumab were discovered using phage display technology. Meanwhile, the anti-interleukin-13 (anti-IL-13) antibody Tralokinumab was discovered using RNA display technology. These drugs have all been approved for clinical use. Display technology has made significant advancements in drug discovery, with several drugs developed through this technology entering clinical trials [27].
Many peptide drug companies have secured a significant position in the peptide drug research field by leveraging their proprietary screening technologies. For example, Bicycle Therapeutics plc, a biopharmaceutical company, focuses on the development of “Bicycle® molecules”—a new class of therapeutics composed of small bicyclic peptides. The company’s unique bicyclic peptide design and synthesis technology is its most representative asset. Through an innovative combination of phage display and chemical cyclization at three cysteine sites, Bicycle Therapeutics has established a structurally stable and highly efficient bicyclic peptide library, forming a distinctive drug discovery platform in the field of targeted therapies [28].
In Japan, PeptiDream Inc. specializes in mRNA display technology, with its core platform RaPID (Random non-standard Peptides Integrated Discovery) system that is used for the high-throughput screening of high-affinity, structurally diverse macrocyclic peptides. This system covalently links each peptide to its encoding mRNA, enabling the precise identification of binding sequences. Combined with PeptiDream’s proprietary FIT (Flexible In Vitro Translation system), RaPID enables the incorporation of a wide variety of non-standard amino acids during peptide synthesis, allowing the construction of peptide libraries with a scale of up to 10¹² unique sequences [29,30]. Due to its high throughput, chemical diversity, and adaptability to various targets, the RaPID system is the core competitive advantage of PeptiDream in the global peptide drug discovery field.
Display technology also holds tremendous potential in the cosmetics field, particularly with the growing trend of peptide-based cosmetics. For instance, in 2018, Malcolm A. Leissring’s team discovered a novel IDE peptide inhibitor, P12-3A, using phage display technology. This cyclic dodecapeptide has been shown to enhance several insulin-induced processes, including the transcription, translation, and secretion of type I collagen in primary mouse dermal fibroblasts, as well as keratinocyte migration in scratch wound assays. With these properties, P12-3A exhibits great therapeutic and cosmetic potential for topical applications [31].
The application of peptides has extended beyond pharmaceuticals into the cosmetic industry. In 1993, the pentapeptide KTTKS, derived from type I procollagen, was identified for its ability to stimulate extracellular matrix production, leading to its adoption in anti-aging skincare products [32]. Similarly, in 1994, substance P antagonists were incorporated into cosmetic formulations, demonstrating their efficacy in improving skin health and appearance. These applications exemplify how pharmaceutical peptides have been repurposed to address cosmetic challenges.
Peptide synthesis has advanced through three distinct methodologies—Classical Solution Peptide Synthesis (CSPS), Solid-Phase Peptide Synthesis (SPPS), and Liquid-Phase Peptide Synthesis (LPPS) [8]. Each represents a significant leap in addressing the challenges of purity, scalability, and sustainability. This evolution reflects the growing demand for efficient peptide production, particularly in pharmaceutical and industrial applications, while aligning with the principles of green chemistry.
CSPS, the earliest method of peptide synthesis, relies on stepwise reactions carried out in solution. The concept dates back to the pioneering work of Fischer and Fourneau in 1901 [14]. A major advancement in peptide synthesis came in 1932 when Bergmann and Zervas developed the first reversible Nα-protecting group, the carbobenzoxy group, which enabled stepwise chain elongation with precise protection and deprotection strategies [33]. CSPS ensures precise control of reaction conditions and allows for extensive purification of intermediates at each stage, yielding products with exceptional purity. However, the process is labor-intensive, requiring significant manual effort for intermediate isolation and characterization and making it inefficient for long peptides or large-scale production [14]. Despite these limitations, CSPS remains valuable for specific applications, such as the preparation of fragments for convergent synthesis, e.g., oxytocin [34].
The introduction of SPPS by Bruce Merrifield marked a paradigm shift in peptide synthesis [35]. By immobilizing the growing peptide chain on a solid resin, SPPS streamlined the process, eliminating the need for intermediate isolation. The synthesis process begins with the attachment of the first amino acid, corresponding to the C-terminal residue, to the solid-phase resin. Following the successful coupling of the amino acid to the resin, the resin is thoroughly washed to remove by-products and excess reagents. Subsequently, the N-terminal protecting group of the immobilized amino acid is removed, typically through deprotection reactions, and the resin is washed again to ensure the removal of residual deprotection agents. The next amino acid is then activated in the presence of a coupling reagent and conjugated to the growing peptide chain on the resin. This cycle of coupling, washing, and deprotection is repeated iteratively until the desired peptide sequence is fully assembled. Finally, all side-chain protecting groups are removed, the resin is washed to eliminate any remaining reagents, and the peptide is cleaved from the resin under appropriate cleavage conditions to yield the final product [35]. SPPS significantly shortened synthesis t
