Volum 18, Issue 5 (2026)

Introduction

The modern biotechnology industry continually faces a range of challenges and limitations associated with the low stability in physiological environments, high renal clearance, and strong immunogenicity of many therapeutic proteins, peptides, and nanoparticles — drug carriers. Among many synthetic polymers developed to overcome these limitations, polyethylene glycol (PEG) holds a particularly important place [1]. The global PEG market was valued at $5.9 billion in 2025 and is projected to grow from $6.2 billion in 2026 to $9.3 billion by 2033, representing a compound annual growth rate of 6.0%. In 2025, the medical segment dominated the market accounting for more than 40% of total revenue. The demand for pharmaceutical PEG, particularly for drug formulations, biopharmaceuticals, and drug-delivery systems, is increasing; it is due to rising investments in biopharmaceutical research and manufacturing [2]. PEG ability to enhance solubility, bioavailability and to stabilize drug formulations makes it an indispensable compound in the production of oral, topical, and injectable medications. In addition, the development of personalized medicine and biologics manufacturing has increased attention to drug-delivery systems, further fueling demand for PEG. Since investments in research and development — particularly, in biologics and biopharmaceutics — continues to grow, the need for PEG as an excipient is also expected to increase [3].

PEG is known to possess numerous unique properties: it increases the solubility of hydrophobic drugs, improves compound stability, and prolongs the half-life of drugs in the body [4]. PEG can function as a steric shield preventing the immune system from recognizing therapeutic agents, thereby making them more difficult to identify and eliminate [5]. Due to its ability to form flexible and biocompatible cross-linked structures, PEG is widely used to create hydrogels, which serve as scaffolds for regenerative medicine [6] (Figure 1). PEG is also used as a coating for implantable medical devices to reduce protein adsorption and cell adhesion to the material surface [7].

Figure 1. Applications of polyethylene glycol (PEG) in biotechnologies and medicine

PEG is known to combine numerous exceptional properties, including high hydrophilicity, flexibility of its polyether chain, and low toxicity, making the polymer the “gold standard” in the field of bioconjugation [8]. Since the approval of the first commercial drugs developed through the PEGylation of therapeutic proteins, this technology has formed the basis of dozens of medications, including PEGylated interferons and liposomal formulations of doxorubicin [9, 10]. Given the extensive use of PEG across various areas of medicine, the information about it remains highly fragmented. The present review summarizes the current understanding of the relationship between PEG chemical structure and its effects on the pharmacodynamic profiles of therapeutic proteins, peptides, drug delivery systems, and tissue-engineered constructs, as well as their behavior in biological systems. In addition, the work considered the aspects of PEG classification and the regulatory framework governing PEGylated drugs.

The literature search was conducted in PubMed, Web of Science, Scopus, and eLIBRARY.RU databases by the following key words: polyethylene glycol, PEGylation, biomedicine, pharmaceutics, and proteins.

Physicochemical properties of polyethylene glycol and its derivatives

Chemical structure of polyethylene glycol

Synthetic water-soluble polymers, including PEG, are widely used in medicine and various industries [11]. Conventionally, each PEG type is designated by a number indicating the polymer average molecular weight. The simplest and most common PEG structures are linear polyethers with two hydroxyl groups at their ends, having the formula HO–(CH₂–CH₂–O)_n–H. The “n” value indicates the number of repeating oxyethylene groups in the molecule (Figure 2) [12]. Ethylene oxide polymerization to produce PEG can be carried out using various methods, including anionic, cationic, and coordination polymerization [13].

Figure 2. Chemical structure of polyethylene glycol (PEG) (adapted from [12] with changes). mPEG — monomethoxy-PEG

Anionic polymerization is the most common method for PEG synthesis because it enables control precisely over the molecular weight and the end-group functionality of the resulting polymer. The synthesis proceeds through the ring-opening polymerization of an epoxide (cyclic) ring of ethylene oxide resulting in Gaussian distribution of PEG with different dispersity and chain length. One of the approaches to producing monodisperse PEG is the chromatographic purification of dispersed PEG. For example, low-pressure displacement chromatography is used to improve the uniformity of low-molecular-weight PEG, enabling to achieve a highly pure polymer with the desired chain length [13, 14].

Since the repeating ethylene oxide units of PEG lack reactive groups, PEG is conjugated to other compounds through terminal functional groups to activate the compound. The terminal PEG groups serve as functional groups in chemical modification reactions; however, their reactivity is relatively low, necessitating the activation of the end groups for the modification of therapeutic proteins and peptides [15]. Monomethoxy-PEG (mPEG) is commonly used for this purpose. Its formula can be represented as CH₃O–(CH₂–CH₂–O)_n–H. mPEG is produced by blocking one of the hydroxyl ends of PEG with a methyl group to prevent cross-linking and agglomeration with therapeutic proteins and peptides during the modification process [15, 16].

In turn, PEG with various end groups can be obtained using appropriate initiators and/or chain-terminating reagents. Thus, a wide range of functional groups can be introduced as PEG end groups including, for example, heterobifunctional products [17, 18]. The unique PEG ability to dissolve in both aqueous solutions and organic solvents makes it suitable for end-group derivatization and chemical conjugation with biological molecules under mild physiological conditions. The studies on PEG in solutions showed this polymer typically to bind 2–3 water molecules per ethylene oxide unit. Due to its highly flexible backbone and its ability to bind water molecules, a PEG molecule behaves as though it were 5–10 times larger than a soluble protein of the comparable molecular weight. This property is precisely why PEG is used to increase the solubility of hydrophobic drugs. PEGylation has no substantial effect on the structural features of a protein, however, it affects its physicochemical properties, including thermal stability [19–22]. PEG can precipitate proteins, exclude proteins from cell surfaces, reduce immunogenicity and antigenicity, and prevent the degradation of compounds caused by mammalian cells and enzymes [23].

Classification of polyethylene glycol derivatives

PEG classification based on molecular weight. PEGs differ in their properties depending on the chain length, compound structure, and molecular weight [24, 25]. Low-molecular-weight PEG (<3500 Da) is often used in pharmaceutics as an excipient or as a component of liposomes/micelles [26]. High-molecular-weight PEG (>5000 Da) is typically used to create complex therapeutic protein constructs. Such polymers may have either linear or branched structure and may be attached to protein molecules in various conformations [10, 27]. The properties of PEGylated proteins also depend, among other factors, on the molecular weight of the PEG moiety. The greater the molecular weight of PEG, the longer the compound half-life and the longer the stability of the modified protein molecule. PEG has low toxicity and is largely not involved in the body metabolic processes. PEG is partially excreted by the kidneys; however, as molecular weight increases, renal elimination decreases, while larger polymers are primarily excreted through the bile [28, 29].

Structure-based PEG classification. The pharmacokinetic profile of a PEGylated protein depends not only on its molecular weight but also on the PEG structure. Moreover, molecular weight and structure are interrelated: molecular weight of linear PEGs typically range from 2 to 40 kDa, whereas branched PEGs generally have higher molecular weight [29]. Depending on its structural conformation, PEGylation can extend the residence time of proteins in the body to varying degrees by protecting them from enzymatic degradation or the recognition by the immune system [24, 30].

Linear PEGs can be either monofunctional or bifunctional. Monofunctional PEGs include methoxy-PEGs as well as active monofunctional PEGs (N-hydroxysuccinimide, maleimides, azides, and others), and their peculiarity is that they contain reactive marks that enable directed binding of a protein molecule at a certain site. Bifunctional PEGs include hetero- and homo-bifunctional PEGs, which are frequently used for the PEGylation of peptides, proteins, and siRNA; the modification of other small molecules; and the development of drug-delivery systems (e.g., nanoparticles). Bifunctional PEGs are polymers with two available sites for protein conjugation, and can therefore be conjugated to two biomolecules. Compared with the original formulation, bifunctional PEGs can substantially increase the viscosity of the final drug product, since a single reactive PEG molecule can conjugate with two different protein molecules resulting in protein cross-linking and hydrogel formation [31]. Branched PEGs are also classified as monofunctional and bifunctional according to their functionality. However, branched PEGs differ substantially in structure. Whereas linear PEGs consist of a single polymer chain, branched PEGs have a central core from which several polymer chains extending. The classification of these PEGs according to their geometry is somewhat conventional; however, the reports in literature most commonly distinguish among Y-shaped, branched, and multi-arm PEGs [32]. Multi-arm PEGs are star-like structures bearing multiple hydroxyl or functional groups, which increase the number of active sites and the molecular weight [33]. The studies of multi-arm and Y-shaped PEGs in protein complexes are limited due to the difficulties involved in analyzing protein cross-linking processes [18, 23]. Nevertheless, multi-arm and Y-shaped PEGs have been extensively studied for the conjugation of small-molecule drugs, such as NKTR-102 (PEG-irinotecan) [34], EZN-2208 (PEG-SN38) [35], and NKTR-214 (PEG-aldesleukin) [36], which are examples of PEGylated drugs that have entered clinical trials. Such PEGs are characterized by a high density of functional end groups. Their distinctive architecture makes branched PEGs particularly effective for constructing highly interconnected polymer networks to form hydrogels [37].

PEG generations. With the development of biotechnology, PEG derivatives have been divided into three distinct generations (see the Table). First-generation, low-molecular-weight PEG derivatives primarily formed bonds with the amino groups of therapeutic proteins and peptides. Significant examples of first-generation derivatives include PEG succinimide carbonate (PEG-SC), PEG benzotriazole carbonate (PEG-BTC), PEG dichlorotriazine, PEG tresylate, PEG p-nitrophenyl carbonate, and PEG trichlorophen. PEG-SC and PEG-BTC are widely used for therapeutic protein modification, since they selectively react with lysine residues within protein molecules, thereby forming carbamates [38, 39]. However, first-generation PEG derivatives often exhibit weak interactions during protein conjugation. As a result, several problems may arise, including the formation of multiple side-reaction and degradation products, as well as the difficulties in separating the modified products. In addition, these derivatives exhibit low stability, high toxicity, and insufficient homogeneity [20].

Characteristics of polyethylene glycol (PEG) generations

Unlike first-generation PEG derivatives, second-generation PEG derivatives use more effective functional groups — aldehydes, esters, and amides — providing more specific and functional chemical modifications. The first second-generation PEG derivative to be discovered was PEG-aldehyde, which has specific properties for modifying the N-terminal amino group of polypeptides. Second-generation PEG derivatives can also perform targeted modification of sulfhydryl groups. Commonly used sulfhydryl-modified PEG derivatives include PEG-maleimide (MAL-PEG), PEG-vinyl sulfone (VS-PEG), and others.

Third-generation PEG derivatives have branched molecular structures. Branched PEG modifications are capable of the site-specific attachment of nanobodies, such as tumor necrosis factor alpha (TNF-α) using branched and Y-shaped PEG. Y-shaped and branched PEG are frequently used in advanced development of TNF-α conjugates. One of the advantages of these structures is their strong shielding effect, which protects the protein from enzymatic degradation and reduces immunogenicity while maintaining a high level of specific activity [16, 23, 40].

PEGylation of proteins

The impact of PEGylation on the pharmacodynamic profile of therapeutic proteins

The interest of biopharmaceutical industry in therapeutic proteins has grown steadily over the past several decades driven by significant advances in genetic engineering. Modern therapeutic proteins have demonstrated high specificity and biological activity. However, despite their numerous undeniable advantages, such proteins are often poorly soluble, unstable, and rapidly cleared from the body. Their outstanding pharmacodynamic profiles are frequently accompanied by poor pharmacokinetic properties, which significantly reduce their therapeutic efficacy [41, 42].

PEGylation is the primary method used to extend the half-life of proteins by protecting them from the body metabolic processes, while having no significant effect on the pharmacodynamic properties of therapeutic proteins [43, 44]. PEGylation can improve the pharmacokinetic properties of therapeutic proteins by extending their circulation time in the body, thereby prolonging the drug therapeutic effect and improving the patient living experience by reducing drug administration frequency.

Protein amino groups have been traditionally used as the primary targets for PEGylation, with acylation or alkylation reactions employed for their modification. However, alternative approaches are becoming increasingly common in modern practice, including PEG attached to thiol, hydroxyl, or amide groups. Specialized chemical or enzymatic methods are used for this purpose.

It should be noted that since regulatory authorities impose strict quality requirements on pharmaceutical products, researchers must thoroughly characterize the resulting conjugates and confirm their purity in accordance with established specifications [45, 46]. Accordingly, general strategies for improving PEGylation selectivity are being actively developed and studied.

Characteristics of therapeutic protein PEGylation

N-terminal PEGylation and lysine PEGylation. PEG is synthesized by the ring-opening polymerization of monomeric ethylene oxide. Water or methanol may serve as an initiator of the polymerization reaction. Initiation with water results in the formation of bifunctional polymer chains. When methanol is used as an initiator, monofunctional PEG is produced. Monofunctional PEG is often preferred for protein conjugation, since it prevents a single polymer chain from linking two proteins [8, 47]. Mono-methoxylated PEG produced by initiation with methanol is typically used as the starting material and functionalized for protein PEGylation. However, a certain amount of dihydroxyl PEG (a bifunctional polymer) is always present in mPEG, resulting in undesirable cross-linking of the reaction products. The diols can be removed by converting the hydroxyl group into a carboxylic acid followed by separating the products using ion-exchange chromatography [48].

For protein conjugation, mPEG is functionalized through its free terminal hydroxyl group. The active moiety is selected according to the reactive groups available on the protein. Commonly used reactive groups include N-terminal amino groups; the C-terminal carboxylic acid; and the residues of lysine, cysteine, serine, threonine, histidine, arginine, glutamic acid, and aspartic acid [44, 49, 50]. Since lysine is one of the most common amino acids in protein sequences, many PEG derivatives have been modified for the corresponding amino groups. Most PEG reagents are designed for amine conjugation, more specifically — for the ε-amino groups of lysine residues. Active esters produced by reacting PEG carboxylic acid with N-hydroxysuccinimide to form succinimidyl-activated esters are the most commonly used acylating agents for protein PEGylation. These esters react with primary amines to form amide bonds. Due to numerous lysine residues in protein amino acid sequences, the initial PEGylation of amines inevitably results in complex mixtures with different degrees of PEGylation. Moreover, improved selectivity can be achieved depending on the reaction conditions (temperature, pH, PEG-to-protein ratio, and reaction time), although such “random” PEGylation invariably leads to the formation of several positional isomers [47].

Nevertheless, nonspecific PEGylation has already proven its efficacy in improving the pharmaceutical properties of therapeutic proteins, promoting the commercialization of PEGylated drugs. For example, Pegasys (F. Hoffmann-La Roche, Ltd., Switzerland) used to treat hepatitis C infection, is produced by nonspecific PEGylation of interferon α-2a with branched 40-kDa succinimidyl PEG [51]. The PEGylation reaction product of interferon α-2a typically contains 45–50% mono-PEGylated protein, approximately 5% poly-PEGylated protein, with the remainder consisting of unreacted protein. The antiviral activity of the conjugated protein was less than 1/10 of the native protein; however, this was largely offset by the increased residence time of the PEGylated drug in the bloodstream, which was up to 20 times longer than that of the native protein [43].

In recent years, there has been a clear trend toward more precise control over the structure of PEGylated therapeutic proteins. Numerous PEG-specific modifications have been developed, and new approaches to the PEGylation of therapeutic protein molecules have been suggested.

Cysteine (thiol) PEGylation. Cysteine PEGylation has demonstrated its efficiency in modifying enzymes and monoclonal antibodies to improve the targeting of tumor cells [52, 53]. The method is based on the specific properties of maleimide. In this case, thiol groups react with PEG-maleimide in neutral or slightly alkaline buffers, forming stable thioether bonds. Site-specific modification of granulocyte colony-stimulating factor (G-CSF) provided the prolonged biological activity of the compound in a neutropenia model in mice. Interestingly, high-molecular-weight PEG was associated with enhanced leukocyte proliferation [54]. PEGylation significantly increases the circulating half-life of G-CSF compared with its native form, and the half-life of PEGylated proteins prolongs with the growing molecular weight of PEG [55]. In addition to G-CSF, thiol PEGylation has been used to conjugate the enzyme L-asparaginase, which is used to treat leukemia. PEGylation increased the hydrodynamic radius of the enzyme, thereby reducing its glomerular filtration rate. Moreover, the conjugation of L-asparaginase with PEG stabilized the enzyme active site and enhanced its catalytic activity [56].

Carboxyl PEGylation. The compounds PEGylated using the carboxyl method demonstrate increased solubility and reduced immunogenicity. Carboxyl PEGylation specifically targets the residues of aspartic and glutamic acids in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC). Initially, COOH group in the protein is activated by EDC converting the carboxyl group into a reactive O-acylisourea form that facilitates its reaction with the primary amino groups of PEG [57]. Carboxyl PEGylation of brain-derived neurotrophic factor (BDNF), which is essential for neuronal survival, growth, and differentiation, improved the peptide pharmacokinetic properties and reduced its plasma and hepatic clearance. An increase in the renal clearance of BDNF-PEG2000 compared with unPEGylated BDNF was also reported, which was attributed to the improved cationic properties of the PEGylated peptide. In contrast, BDNF-PEG5000 showed reduced elimination from the body, highlighting the important role of PEG molecular weight in drug development [58].

PEGylation is a powerful tool for creating new protein therapeutics resulting from its ability to extend half-life, improve solubility, and reduce the rate of degradation and elimination of PEGylated proteins from the body. However, PEGylation can negatively affect a protein active site or overall structure and can also alter its bioactivity; therefore, selecting an appropriate modification method is essential for preserving protein functionality [18, 59, 60].

Polyethylene glycol as a solvent and functional excipient in pharmaceutics

In pharmaceutics, PEG can be compared to a “universal assistant” that optimizes the properties of other substances by helping them mix better, dissolve, or acquire the desired consistency.

The key value of PEG lies in its ability to increase the solubility of active pharmaceutical ingredients and drug products, thereby improving their absorption by the body. This property of PEG is of particular importance for compounds classified under the Biopharmaceutics Classification System (BCS), which categorizes substances according to their aqueous solubility and permeability to the intestinal wall, as Class II (low solubility, high intestinal permeability) and Class IV (low solubility, low intestinal permeability) [61]. PEG helps solve this issue in several ways.

First, PEG acts as a cosolvent: due to its polarity, it reduces the overall polarity of the solvent–drug system and facilitates the dissolution of hydrophobic molecules. Liquid PEGs (e.g., PEG 200–600) are used in oral and parenteral dosage forms. Notably, PEG 300 and PEG 400 are approved to be used in parenteral formulations at concentrations of up to 30% v/v [62].

Second, PEG participates in micellar solubilization. During micelle formation, the hydrophobic drug is retained in the core, while the hydrophilic PEG shell ensures solubility in an aqueous medium. Currently, PEG copolymers with such hydrophobic polymers as PLGA, PCL, and others are considered particularly promising. These copolymers self-assemble into nanoscale core–shell structures capable of solubilizing not only small molecules but also proteins and peptides. For example, Genexol-PM (Samyang Pharmaceuticals, South Korea) is a clinically approved nanoparticulate chemotherapeutic drug with a controlled release profile — it is a polymeric micellar composition of paclitaxel and PEG. The drug is approved in South Korea to treat breast cancer, it contains mPEG-PDLLA block copolymer (polyethylene glycol monomethyl ether — poly(D,L-lactide) block polymer) and paclitaxel, which is “hidden” within the hydrophobic core of the micelles [63].

Third, PEG is used in solid dispersions, which consist of a hydrophilic matrix containing the active ingredient dispersed at the molecular level and incorporated into a carrier — in this case, PEG. The use of PEG increases the bioavailability of drugs in solid dispersions. For example, metronidazole solubility in a solid dispersion increases by 14–17% compared with the initial substance. In this case, PEG with a molecular weight of 1500 g/mol is used, and the optimal component ratio in the solid dispersion (metronidazole:PEG) is the mass ratio of 1:1 [64]. There are the examples of commercially available pharmaceutical products based on solid-dispersion technology. For instance, Fenoglide (Salix, USA) (its active ingredient fenofibrate belongs to Class IV according to BCS) and Nimotop (Bayer, Germany) (its active ingredient nimodipine belongs to Class II according to BCS) contain PEG as a carrier [65].

PEG is known to help stabilize the drug formulations and extend their shelf life. Equally important is its role in creating the desired texture and consistency of the finished product — this is crucial for the ease of use and predictable dosing. The molecular weight, chain length, and chemical composition of PEG terminal groups affect its solubility, hygroscopicity, compatibility, and miscibility with other excipients and active pharmaceutical ingredients [4]. For example, PEG chain mobility increases as molecular weight decreases; therefore, low-molecular-weight PEGs can be used as plasticizers in solid dispersions and film coatings, increasing the flexibility of tablets and preventing their brittleness. In contrast, high-molecular-weight PEGs are crystalline substances, which can act as matrix-forming agents, reducing the dissolution rate, and they can be used in extended-release systems. Thus, combining PEGs with different molecular weights enables to control drug-release kinetics [66].

This polymer is incorporated into a variety of dosage forms ranging from liquid injectable solutions and suspensions to thick creams and ointments. It is used in injectable formulations, solutions, solid and effervescent tablets, capsules, sublingual tablets, oils, lotions, gels, and ointments. D’Souza and Shegokar summarizing the data on known PEG-based preparations [62] showed the applications of this polymer to depend on its average molecular weigh. Low-molecular-weight PEGs are primarily colorless, viscous liquids used in injections, suspensions, and solutions, whereas high-molecular-weight PEGs are primarily solid, waxy substances widely used in tablets, capsules, and suppositories.

Due to the incorporation of PEG into drug formulations, the active ingredients are absorbed more effectively, resulting in a more pronounced therapeutic effect. In oncology, for example, PEG enables more precise delivery of a drug to tumor tissues: it helps keep the drug in the bloodstream longer and reduces its toxic effects on healthy cells. This property of PEG is used in targeted drug delivery, which will be discussed in greater detail in the following section.

Polyethylene glycol as a component of a targeted drug delivery system

As a key component of modern drug delivery systems, PEG forms a protective barrier around the active substance and prevents its premature degradation in the body, thereby prolonging its action. In this context, the primary function of PEG is to create a hydrophilic, hydrated shell around a hydrophobic core. This shell serves several functions at once: it stabilizes the dispersion, masks the particles from the immune system, and enables targeted drug delivery. The best-known effect of PEG is referred to as the “stealth effect” [62, 67]. In general, the reticuloendothelial system rapidly recognizes and removes foreign particles from the bloodstream. A PEG shell prevents this process by forming a dense, hydrophilic “protective” layer, reducing the surface charge density, and thereby masking the particle shape and surface creating steric repulsion, and reducing protein adsorption. As a result, drugs circulate in the blood longer, and are accumulated more effectively in target tissues (e.g., in tumors, due to the enhanced permeability and retention effect). Drug delivery systems may include PEGylated nanoparticles, liposomes, proteins, enzymes, small-molecule drugs, polyelectrolytes, and others [68].

Liposomes are among the most extensively studied carriers used in targeted drug delivery systems. Liposomes are spherical lipid vesicles (typically 50–500 nm in diameter) consisting of one or more lipid bilayers. Liposomes are resulted from the emulsification of natural or synthetic lipids in an aqueous medium [69]. The main advantage of liposomes is their ability to encapsulate a wide range of substances with virtually no restrictions regarding their chemical nature, molecular size, and properties providing a unique tool for addressing numerous medical challenges [70]. The only problem in using conventional liposomes in vivo is that they readily adsorb opsonin molecules onto their surface. It leads to the recognition and uptake of liposomes by the reticuloendothelial system cells followed by their rapid removal from the bloodstream. To prevent rapid recognition by the reticuloendothelial system, liposome surfaces are modified with hydrophilic polymers such as PEG. This modification reduces interactions with serum opsonins and increases the circulation time of liposomes in the bloodstream. For example, the study by Jyothirmayi et al. [71] showed increasing the proportion of PEG on the liposome surface to 4–10% to result in a substantial increase in in vivo circulation time — from 200 to 1000 min. The development and study of PEG-coated liposomes have demonstrated their strong potential for clinical applications [70]. Doxorubicin, for example, is one of the most extensively studied drugs delivered by PEGylated liposomes. The PEG coating not only protects liposomes from phagocytosis but also substantially increases the encapsulation efficiency, which reached 98% in some studies. In the study by Minamisakamoto et al. [72], spherical liposomes were coated with PEG-DSPE to deliver doxorubicin in vivo. In that case, PEG acted as a stabilizer for doxorubicin, and enhanced its permeability, thereby increasing the effectiveness of liposomes as drug delivery systems [4, 72].

Considerable experience has been accumulated in using PEG-coated nanoparticles for systemic delivery. These systems help overcome biological barriers and are used to treat numerous diseases. At the same time, researchers carefully analyze both the various physicochemical parameters of PEG-coated nanoparticles (the molecular weight of PEG, its surface density, and the characteristics of the nanoparticle core) and the specifics of the administration regimen. In the study by Dunn et al. [73], the particles with different PEG surface densities were investigated; the particles were produced through the copolymerization of styrene with the PEG macromonomer PS-PEG (polystyrene–poly(ethylene glycol)). An in vivo study devoted to the biodistribution of PS-PEG particles after intravenous administration to rats demonstrated a relationship between PEG surface density and the length of time the particles remained in the bloodstream while evading the recognition by the reticuloendothelial system. The particles with a higher PEG surface density exhibited longer circulation times in the bloodstream.

A key factor determining the in vivo behavior of PEG carriers is their interaction with plasma proteins. This interaction determines how long the particles circulate in the bloodstream and how actively they are taken up by immune cells. Gref et al. [74] described the development of the so-called stealth particles, their cores consisted of a biodegradable polymer (polylactide — PLA, poly(lactide-co-glycolide — PLGA, or polycaprolactone — PCL), with PEG chains covalently attached to the core surface. The main objective of the study was to optimize the parameters of the “corona” (the thickness and density of the PEG layer) as well as the composition of the core in order to achieve two goals simultaneously: reduce particle uptake by phagocytic cells (i.e., decrease their recognition and capture by immune cells) and reduce the adsorption of blood plasma proteins. The detailed analysis revealed the optimal parameters for the PEG coating: the greatest reduction in protein adsorption was achieved with a PEG molecular weight of 5000 g/mol, while the threshold PEG content providing maximum resistance to adsorption was 2–5 wt% (a further increase in the PEG fraction produced no additional effect). Phagocytosis studies using chemiluminescence methods and zeta-potential measurements were in good agreement with these findings. It was established that a threshold PEG surface density was found to simultaneously provide effective steric stabilization and prevent particle uptake by polymorphonuclear neutrophils [74]. The study by Muralidharan et al. [75] demonstrated the preferential use of PEG 3000–PEG 5000 in the development of long-circulating nanoparticles.

Polyethylene glycol as a foundation for polymers-based solutions in regenerative medicine

PEG is known to serve as a base for creating specialized polymeric materials used to address a range of medical challenges. One of the most promising forms is biocompatible hydrogels, they are able to mimic the physical properties of living tissues and widely used in regenerative medicine to accelerate the healing of damaged organs and tissues. According to the definition approved by the International Union of Societies for Science and Engineering in Biomaterials, “regenerative medicine comprises methods for treating diseases, congenital conditions, or injuries by regenerating functional tissues or organ structures” [76]. One of the objectives of regenerative medicine is to create new tissues outside the body by combining biomaterials with living cells. To interact effectively with cells and stimulate tissue formation, the materials used must mimic the natural tissue environment and exhibit biological activity, which is crucial for maintaining cell adhesion, proliferation, and differentiation [77].

PEG-based materials are well suited to these tasks, since they can be deliberately modified to impart the desired biological properties. Owing to the flexibility of chemical structure, PEG-based materials can reproduce the key characteristics of the cellular microenvironment, including the mechanical, hydrophilic, and spatial parameters that are important for cell behavior.

In practice, PEG-based matrices have already demonstrated their effectiveness in forming various types of tissue. Such materials have been used to create the models of cartilage, bone, vascular, endometrial, liver, and cardiac tissue, as well as tumor tissue models [77–79]. For example, Betz et al. [80] presented a thermosensitive PEG gel — the biomaterial composed of 5-ethyl-5-(hydroxymethyl)-β,β-dimethyl-1,3-dioxane-2-ethanol diacrylate (EHD) and poly(ethylene glycol) diacrylate (PEGDA) incorporating bone morphogenetic protein 2. The gel supported the growth of bone marrow stromal cells, resulting in their differentiation and deposition of bone matrix. The study by Fu et al. [81] showed a biodegradable triblock copolymer of poly(ethylene glycol)-poly(ε-caprolactone)-poly(ethylene glycol) (PEG-PCL-PEG, PECE) containing collagen and nanohydroxyapatite to direct bone-tissue regeneration. The resulting nanocomposites had a three-dimensional network structure and proved to be promising materials for injectable orthopedic applications and tissue engineering due to their favorable thermosensitive properties and injectability. Huang et al. [82] demonstrated that RGD peptide (arginine-glycine-aspartic acid) immobilized on a bioinert PEG nanostructure formed adhesion sites for osteoblasts and supported binding through integrin receptors. Quizon et al. [83] on a porcine model, obtained the evidence of robust vascularization and perfusion in the subcutaneous space induced by synthetic hydrogels based on a PEG macromer functionalized with 4 maleimide groups (PEG-4MAL) and delivering VEGF. The study by Kraehenbuehl et al. [84] demonstrated synthetic three-dimensional (3D) PEG-based hydrogels responsive to matrix metalloproteinases to be able to direct the in vitro differentiation of pluripotent embryonal carcinoma cells along the cardiac line. The authors concluded that this 3D system could serve as an alternative to natural matrices for creating cardiac tissue structures and could potentially be used in therapy.

It should be noted that PEG-based hydrogels themselves possess no biological activity, since they lack reactive sites providing the interactions with cellular receptors. At the same time, they can be modified by attaching peptide sequences and growth factors, which help cells attach and perform their functions by providing the necessary signals and regulation. As a result, the hydrogel becomes more than just a neutral 3D matrix; it becomes an environment that actively supports cell viability, adhesion, proliferation, and even differentiation [85].

Another application of PEG in regenerative medicine is using PEG not as a scaffold material but as an auxiliary agent for the PEGylation of matrix components intended for biomedical applications. The covalent attachment of PEG molecules to biopharmaceutical molecules is known to improve the pharmacological and therapeutic properties of proteins and other macromolecules. This approach is currently in high demand [46]. For example, FUD (functional upstream domain) peptide as an antifibrotic agent, and its PEG-modified form with improved pharmacokinetic properties are being used in experimental fibrosis models and in antifibrotic therapy [86]. PEGylation of nanomaterials has been effectively used for controlled drug delivery and regenerative therapy in retinal diseases. The process improves stability and reduces the immune response in the ocular environment, while peptide functionalization enables specific cellular targeting and minimizes inflammatory reactions [87]. Chu et al. [88] described the role of PEG as a linker that helps integrate graphene oxide and quercetin into a matrix. The hybrid scaffold based on a dermal matrix, PEGylated graphene oxide, and quercetin (GO-PEG/Que) offers multiple advantages, including biocompatibility with a cell-adhesive surface, which accelerates the attachment and proliferation of mesenchymal stem cells, as well as high stability and tunable conductive properties during wound healing in diabetic patients. According to the authors, the study opens new opportunities for developing GO-PEG-based hybrid collagen matrices for applications in tissue engineering and regenerative medicine.

In our study [89], the composite designed to form a biopolymer hydrogel scaffold carrier, containing PEGylated plasma cryoprecipitate proteins and type I collagen, demonstrated favorable results in repairing an experimental full-thickness excisional wound in a pig. During the early stages of the regenerative process, the biopolymer hydrogel scaffold was shown to integrate into the tissue, promote cell recruitment, support cellular proliferative activity, and accelerate the maturation of granulation tissue. At later stages, the scaffold was also able to prevent scar tissue formation.

Thus, PEG-based materials remain a promising platform for tissue engineering: their tunable properties allow the matrix to be flexibly adapted to different tissue types and to specific research or therapeutic objectives.

Polyethylene glycol as a component of cosmetic and dermatological products

PEGs are frequently used in dermatological and cosmetic formulations. These polymers are also used in cosmetic products as surfactants, emulsifiers, cleansers, and skin-hydrating agents. They are added to creams, lotions, and cleansing formulations to improve the product sensory properties: creating a more pleasant texture, ensuring smooth application, and enhancing hydration [90].

Moreover, PEG can enhance the delivery of active ingredients into the skin. In anti-aging products, it acts as an effective carrier: it helps ingredients such as retinol and peptides to penetrate deeper layers of the skin and fully exert their effects. This increases the overall efficacy of the product and allows the desired cosmetic results to be achieved more quickly. PEG and its derivatives are generally considered safe to be used in cosmetics.

Polyethylene glycol as a preparatory agent for diagnostic procedures

In medicine, PEG is frequently used to prepare the bowel for diagnostic procedures. The use of an aqueous electrolyte PEG solution for bowel cleansing was first proposed by Davis et al. in 1980 [91]. The isotonic oral solution used by the authors was neither digested nor absorbed in the intestine. Currently, a therapeutic regimen involving 4 L of PEG is widely accepted for patient preparation before such procedures. PEG is an osmotic laxative that is not absorbed in the intestine. An important advantage of PEG preparations is that their use cause no significant changes in water and electrolyte balance [92].

PEGylation and legal regulation of PEGylated pharmaceuticals

The section considers the concept of PEGylation in greater detail from the perspective of the regulatory requirements applicable to PEGylated products, as well as the legal considerations concerning the use of PEGylated biopharmaceuticals.

PEGylation is the chemical modification of biomolecules through the attachment of one or more chains of activated PEG [62, 93, 94]. The substrates most commonly used for PEGylation include proteins, peptides, low-molecular-weight compounds, or oligonucleotides [31, 95], resulting in a new molecular structure, its physicochemical and physiological properties differing substantially from those of the original molecule [5]. Currently, PEGylation has evolved beyond a simple drug-delivery technology and has become an important tool for the targeted modification of pharmaceutical products. The approach can substantially improve the clinical efficacy of existing biopharmaceuticals [12, 29]. Following PEGylation, the molecule acquires several advantages: its pharmacokinetic properties improve (e.g., its half-life is extended and its clearance rate is reduced) and its pharmacodynamic characteristics are enhanced, including greater stability of action and more predictable effects [5, 46]. It enables to achieve a more pronounced therapeutic outcome.

One of significant advantages of PEGylated drugs is their ability to produce a sustained clinical effect at lower doses and with less frequent administration. Such approach improves patient quality of life by simplifying treatment regimens and reducing the overall time and cost of therapy [96].

From a contemporary legal perspective, PEGylated drugs are no longer assessed solely on the basis of their individual ingredients. Once a molecule is bound to a chemical component, the resulting conjugate becomes a new chemical entity, since the pharmacodynamics and pharmacokinetics of the conjugated component have been altered [45]. Accordingly, a PEGylated product should undergo all the necessary approval stages required for new medicinal products. The stability, toxicology, and biological fate of the PEGylated product must be established before it is placed on the market [45, 97]. The rapid growth in research in this field is expected to expand the range of PEGylated products available in the medical market. At the same time, it is emphasized that the regulatory framework should be adapted to reflect the advances in nanomedicine while ensuring patient safety [97, 98]. By 2022, 12 PEGylated biopharmaceutical products had been approved by the FDA in the United States demonstrating the clinical significance of the technology [46]. As of 2026, more than 30 types of PEGylated drugs are used in clinical practice [99], while many others are undergoing clinical trials. At present, more than 80 active clinical studies of such products are being conducted [10, 100–103].

In Russian legislation there is no separate federal law devoted exclusively to PEGylated drugs. In practice, however, the use of these drugs is regulated through the general rules governing the registration and description of medicinal products established by Decision No.18 of the Council of the Eurasian Economic Commission, dated February 21, 2025. The document amends the requirements for the instructions for medical use and the summary of product characteristics. It expressly provides that the specific provisions set forth in Appendix No.2 to these requirements should be taken into account for PEGylated drugs [104]. According to this appendix, when a PEGylated drug is registered in Russia (or in any other country of the Eurasian Economic Union), the composition of the drug should be described in detail, including the information about the attached PEG chain. Moreover, the PEG molecule attachment itself should be characterized in detail: the degree of modification is to be specified (i.e., how many PEG molecules are attached to each protein molecule), as well as the pattern of modification, including the specific sites on the protein wh ere the reaction occurred. The physicochemical, immunochemical, and biological properties of the resulting conjugate must also be described. Since PEGylation alters the properties of the molecule, a detailed description helps physicians and regulators better understand the drug profile, as well as its benefits and potential risks [27, 105, 106].

Conclusion

The review presents the information on the role of PEG and its derivatives in modern pharmaceutics and medicine. The analysis of PEG physicochemical properties — including the features of its chemical structure and the diversity of its derivatives classified by molecular weight, structural organization, and other parameters — provides a foundation for understanding the mechanisms underlying its broad practical application.

The range of medical applications of PEG demonstrates its versatility: it is used as a solvent and functional component in pharmaceutical formulations, as a key element in targeted drug-delivery systems and regenerative medicine solutions, in the manufacture of cosmetic and dermatological products, and in preparing patients for diagnostic procedures.

The regulatory aspects of using PEGylated drugs deserve particular attention. Compliance with the applicable legal and regulatory framework, including the provisions established by the decisions of the Council of the Eurasian Economic Commission is a mandatory condition for the development, registration, and safe use of these medicinal products.

Thus, PEG is a multifunctional tool in modern medicine. Its versatility results from the ability to tailor its properties through molecular weight, density, bond type, and combinations with other polymers.

Author contributions. All authors made equal contribution to writing the present paper.

Study funding. The work was supported by the Russian Science Foundation grant No.26-13-00582.

Conflict of interest. The authors declare no conflict of interest related to the present study.