Polysaccharide-Modified Liposomes: Advances in Surface Engineering for Targeted Drug Delivery

Abstract

Liposomes remain one of the most utilized drug delivery systems due to their numerous advantages. However, they face significant challenges primarily due to their low colloidal stability as well as their rapid clearance by the reticuloendothelial and mononuclear phagocyte systems. Surface modifications have been identified as a highly effective approach to address these challenges. Various molecules can be utilized as surface modifiers. However, polysaccharides are widely employed in this regard, due to their unique characteristics, such as biocompatibility, biodegradability, and non-toxicity, as well as their ability to interact with the liposomal surface through different mechanisms. The aim of the present review is to provide a thorough analysis of polysaccharide-modified liposomes, highlighting recent advancements in their design, synthesis, and therapeutic applications. The utilization of polysaccharides as surface modifiers has been demonstrated to have several notable effects on liposomes. These effects include the enhancement of liposome properties, the provision of “stealth” properties, and the augmentation of colloidal stability. This review provides a comprehensive, polysaccharide-oriented analysis of liposomal surface modification strategies, along with a novel focus on the correlation between polysaccharide structure, modification method, and the resulting physicochemical and biological performance of the designed hybrid liposomes across a wide range of applications.

1. Introduction

The effective delivery of active agents remains a significant challenge in the therapy of multiple conditions. Conventional drug formulations have several limitations, such as poor bioavailability, rapid enzymatic degradation, non-specific distribution, and systemic toxicity. To overcome these limitations, the field of nanotechnology has been widely utilized. The nanocarriers offer a wide range of possibilities, such as encapsulation of a variety of drugs, protection from harsh conditions (i.e., gastric media), as well as prolonging their circulation and improving targeting efficacy [1].

Among all nanocarriers, liposomes emerge as a highly successful and clinically relevant carrier. They are spherical vesicles, composed of one or more lipid bilayers, surrounding aqueous core. Their unique structure allows them to efficiently encapsulate both hydrophobic and hydrophilic substances. Key advantages of liposomes include their biocompatibility, low immunogenicity and relative similarity to the cell membranes [2].

However, conventional, or unmodified, liposomes impose substantial challenges, mostly due to their rapid uptake by the cells of the reticuloendothelial system (RES) and mononuclear phagocyte system (MPS), leading to shortened presence in the bloodstream, which limits their accumulation at the target site. The rapid clearance of the liposomes requires the implementation of different strategies, that can prevent the liposomes from being recognized and targeted by the cells of RES and MPS [3].

Surface engineering has proven to be a viable strategy to overcome these limitations. The utilization of different biopolymers, such as polysaccharides, as coating materials has become a particularly promising approach [4]. Polysaccharides are suitable candidates for this purpose, due to their unique set of characteristics, including high biocompatibility, extensive structural variety and the presence of functional groups that can facilitate efficient conjugation to the liposomal surface. The polysaccharide coatings can provide several distinct functions, such as prolonged systemic circulation (“stealth” effect), increased physical and chemical stability, enhanced targeting potential (Figure 1).

The hydrophilic polysaccharide coating effectively inhibits the adsorption of opsonin proteins, thereby reducing the recognition and rapid uptake by the RES. This creates the so called “stealth effect”, allowing liposomes to reach the target area more efficiently [5]. Due to the characteristics of the polysaccharides, the coatings function as a physical barrier, preventing liposomes aggregation and fusion. This significantly improves their physical stability during storage. Moreover, the polysaccharide shell significantly minimizes the contact of the liposomes membrane with external factors enhancing the chemical stability and reducing premature drug leakage [6]. The presence of numerous functional groups on the polysaccharides allows them to bind to different targeting ligands (i.e., low-molecular citrus pectin can bind to Galectin-3 receptors [7]). Additionally, these polysaccharides can be employed as platforms for conjugating other targeting molecules, which is also extensively used in the scope of targeted therapy [8].

The current review aims to examine the recent advancements in the design, synthesis, characterization and therapeutic application of polysaccharide-modified liposomes. Several recent reviews have addressed liposomal surface modification strategies or the application of polysaccharides in nanomedicine, often focusing on specific therapeutic areas or individual functional outcomes. However, these reviews typically adopt either a formulation-driven or application-oriented perspective, which limits direct comparison across different polysaccharide classes. The present review addresses this gap by organizing and analyzing the literature from a polysaccharide-centered perspective, with a focus on the correlation between polysaccharide structure, modification method, and the resulting physicochemical and biological performance of the designed hybrid liposomes. By integrating and comparing data across multiple polysaccharide types within a unified framework, this review aims to provide deeper insight into structure–function relationships that can guide the rational design of polysaccharide-functionalized liposomal systems.

2. Materials and Methods

The literature search was conducted using PubMed, Web of Science, ScienceDirect, and Google Scholar databases. The search strategy employed combinations of keywords including “liposomes,” “polysaccharide-modified liposomes,” “polysaccharide-coated liposomes,” “surface modification,” “layer-by-layer,” “chemical conjugation,” and “targeted drug delivery.” The initial search identified 211 publications. After screening titles and abstracts, articles were assessed based on predefined inclusion and exclusion criteria. Inclusion criteria comprised original research articles reporting the preparation, characterization, or biomedical application of polysaccharide-functionalized liposomes. Exclusion criteria included studies not involving liposomal systems, non-polysaccharide surface modifications, and articles lacking experimental data. Based on these criteria, 55 original research articles were identified as directly relevant to polysaccharide-functionalized liposomes and formed the core basis of this review. Selection criteria as PRISMA 2020 flow diagram [9] are provided as Supplementary Materials (Figure S1). Review articles were consulted selectively to support established background concepts and methodological context. The present review includes a total of 171 cited references, with the majority of the included sources published within the last five years (Figure 2).

3. Surface Modification of Liposomes: Methods, Interactions and Functions

Surface modification of liposomes is a central strategy for optimizing their physicochemical stability, circulation behavior, drug release, and biological performance. Current approaches rely on chemical conjugation, surface deposition, and polymer cross-linking, while the resulting interactions between the coating agents and lipid bilayer ultimately define the functional outcomes of these modifications.

3.1. Methods of Surface Modification

A variety of modification approaches have been developed to enhance liposomal stability, prolong systemic circulation, and introduce specific functionalities such as targeting or controlled drug release. These methods can be broadly classified into chemical conjugation-based techniques, surface deposition approaches, and polymer cross-linking strategies, each relying on different types of interactions between the liposome membrane and the modifying agents (Figure 3).

Chemical conjugation involves covalent attachment of functional molecules to membrane components, most commonly cholesterol or phospholipids such as phosphatidylethanolamine [10]. Cholesterol enhances membrane rigidity and storage stability while providing multiple reactive sites [11]. Direct carbodiimide-mediated conjugation enables attachment of carbohydrates, metal complexes, or peptides, improving circulation time, targeting, or diagnostic functionality [12,13,14]. Alternatively, linker-based strategies, including click chemistry and PEG-mediated conjugation, are widely used to produce stealth and targeted liposomes, frequently employing folic acid or PEG derivatives [15,16].

Surface deposition methods rely on non-covalent interactions such as electrostatic, hydrogen, and van der Waals forces. These approaches are simple and versatile but sensitive to coating concentration and interaction strength, which influence membrane permeability, drug release, and aggregation behavior [17,18,19,20]. The layer-by-layer (LbL) technique enables sequential deposition of oppositely charged polymers, allowing controlled shell thickness and multifunctionality, including steric stabilization, targeting, and prolonged circulation [21,22]. Multilayer formation is driven by entropy gain from counterion release and charge overcompensation, although heterogeneous coating structures and polymer charge density strongly affect stability and performance [23,24,25].

Polymer cross-linking is applied to stabilize water-soluble or weakly bound coatings by forming chemically cross-linked shells. This significantly improves mechanical and osmotic stability, even after lyophilization, but may alter drug release kinetics [26]. Cross-linked polymer shells are particularly advantageous for targeted delivery and stimulus-responsive systems, such as protease-triggered release in tumor environments [17].

3.2. Interaction Mechanisms Between Coating Agents and Liposomes

Coating agents may interact with liposomes through surface deposition, incorporation into the lipid bilayer, or hybrid mechanisms. Surface interactions involve covalent or non-covalent bonds and can occur on the inner or outer membrane surfaces depending on the modification stage [27]. While covalent bonds offer high stability, they may hinder drug release, whereas weaker interactions can compromise long-term stability [28,29,30]. Incorporation into the lamellar structure occurs primarily through hydrophobic interactions between lipid acyl chains and amphiphilic modifiers, enhancing membrane rigidity and drug retention. Cholesterol and other hydrophobic additives are commonly used for this purpose [27,31]. Hybrid interactions arise when modifiers are both embedded within the bilayer and deposited on the surface, particularly in cross-linked or composite systems, combining high stability with functional versatility [32].

3.3. Functional Outcomes of Surface Modification

Surface modification governs the biological fate of liposomes by improving colloidal stability, reducing premature drug leakage, and prolonging systemic circulation (Figure 4) [33,34]. The improved colloidal stability can be achieved via two main mechanisms: steric stabilization and electrostatic repulsion. Steric stabilization can be observed when the polysaccharide chains form a protective shell on the surface of the liposomes, which reduces the forces of attraction (i.e., van der Waals) that lead to the agglomeration of the uncoated ones [5,35]. Furthermore, polyelectrolyte coating, such as chitosan and alginate, impart a high surface charge, creating a strong Debye double layer, which repels the particles from each other [36]. A major objective is evasion of the reticuloendothelial system, most commonly achieved through PEGylation, which confers stealth properties and significantly extends circulation time [37,38,39,40,41,42]. However, excessive PEG content may reduce cellular uptake, prompting the development of stimuli-responsive PEG-based systems. For example, Momekova et al. (2007) developed pH-sensitive liposomes sterically stabilized with PEG-based copolymers, demonstrating prolonged circulation time while maintaining pH responsiveness [43]. This work addresses a common limitation of pH-sensitive liposomes—rapid clearance by the reticuloendothelial system—by integrating steric stabilization without compromising stimulus responsiveness. However, the complexity of the copolymer architecture may limit scalability and warrants further investigation regarding long-term reproducibility and manufacturing robustness. Although PEG is commonly used to impart stealth properties to liposomes by reducing protein adsorption and prolonging circulation time, repeated administration may induce anti-PEG antibodies, leading to accelerated blood clearance, reduced therapeutic efficacy, and occasional hypersensitivity reactions [44]. Findings indicate that specific polysaccharide coatings have the potential to circumvent the Accelerated Blood Clearance (ABC) phenomenon, thereby maintaining prolonged circulation profiles over repeated dosage regimens without inducing the potent adaptive immune response observed with PEG [45]. Apart from this, polysaccharides possess an inherent biodegradability, undergoing a process of enzymatic hydrolysis into non-toxic metabolites that can be expeditiously excreted or utilized by the host metabolic pathways. This biodegradability significantly mitigates the risk of tissue accumulation and chronic toxicity [46,47].

Surface modifications also enable controlled and stimulus-sensitive drug release. Commonly, most of the polysaccharides create dense, viscous, hydrogel-like structure on the surface of the liposomes, which can lead to a decrease in the diffusion coefficient of the drug, sufficiently extending the drug release [48]. Endogenous triggers such as pH and temperature are widely exploited in tumor-targeted delivery, often using pH-sensitive phospholipids or polymers that destabilize membranes under acidic conditions [49,50,51,52,53,54]. Certain polysaccharides, such as chitosan, can undergo a protonation of their amino groups (-NH2) to -NH3+, particularly when the pH drops below its pKa value (~6.5). This generates a massive internal repulsion, which causes the polymer chains to uncoil and swell, disrupting the liposomal bilayer and generating pores through which the drug can be released [36,55]. Thermosensitive liposomes employ lipids with defined phase transition temperatures or polymer modifiers that induce rapid drug release upon heating [56,57,58]. Although native polysaccharides do not possess thermosensitive properties, some modified derivatives (i.e., Hydroxypropyl cellulose) exhibit Lower Critical Solution Temperature (LCST). Above the LCST, they undergo a hydrophilic-to-hydrophobic phase transition, leading to a collapse of their structure [59]. This shift could alter the liposomal membrane, changing the release of the incorporated drug, based on the local thermal environment [60,61]. Dual-responsive systems combining pH and temperature sensitivity further enhance release selectivity [62]. Exogenous stimuli, including ultrasound, light, and magnetic fields, are enabled by incorporation of inorganic components, allowing for externally controlled release and imaging capabilities [63,64].

Active targeting is achieved by decorating liposomes with ligands such as aptamers, proteins, lectins, or antibodies, enabling selective interaction with tumor-associated receptors and reducing systemic toxicity [49,65,66,67,68,69,70,71,72,73,74]. Some polysaccharides can act as natural ligands that bind to a specific targeting site. One of the most prominent examples is the binding of hyaluronic acid to CD44 receptors [75]. In this regard, hyaluronic acid-modified liposomes have been broadly utilized as a carrier of antitumor medicines, which can selectively bind to CD44 receptors, triggering receptor-mediated endocytosis [76,77]. Other polysaccharides such as mannan or galactose derivatives can target specific lectins found on the surface of the macrophages or hepatocytes, facilitating targeted up-take by specific organ systems [78,79]. Additionally, surface-modified liposomes can be engineered to overcome biological barriers. Mucoadhesive coatings prolong residence time on mucosal surfaces, improving oral, pulmonary, vaginal, and ocular delivery [80,81,82,83,84,85]. Targeted surface modifications also facilitate transport across restrictive barriers such as the blood–brain barrier and conjunctiva, significantly enhancing tissue accumulation of therapeutics [86,87,88,89].

4. Polysaccharides Used for Surface Modification of Liposomes

Polysaccharides represent one of the most extensively studied classes of biopolymers for the surface modification of liposomes, owing to their structural diversity, biocompatibility, and wide range of functional properties. Depending on their molecular structure, charge, and degradation behavior, polysaccharides can impart distinct characteristics to liposomal systems, including enhanced stability, mucoadhesion, controlled or site-specific drug release, active targeting, and immunomodulatory effects. Among the various polysaccharides investigated, chitosan, alginate, dextran, pectin, hyaluronic acid, fucoidan, β-glucans, and cellulose derivatives are the most commonly used for liposomal surface coating, due to their well-characterized physicochemical properties and proven performance in drug delivery applications (Figure 5). Their natural origin and the presence of multiple functional groups enable versatile interactions with liposome membranes through electrostatic, hydrogen-bonding, hydrophobic, or covalent mechanisms.

4.1. Chitosan

Chitosan is a polycationic biopolymer derived from chitin, which is composed of β-(1–4)-N-acetyl-D-glucosamine, with a structure similar to that of cellulose, but with the difference that chitin has an acetamide group at the C-2 position instead of the -OH group found in cellulose. Chitosan is soluble in acidic to neutral pH, but insoluble in alkaline (pKa—6.5). Due to the presence of numerous intra- and intermolecular hydrogen bonds between the chains of chitosan, the more its molecular weight increases, the slower it dissolves [90]. Chitosan has mucoadhesive properties, which are realized due to the formation of ionic and electrostatic bonds with mucous membranes, especially at pH < 6, at which the amino groups of chitosan are protonated and interact with the negatively charged groups of mucin (-COO⁻ and -SO₄ ²⁻) [91].

Thanks to these characteristics, chitosan is widely used as a carrier for various macro-, micro- and nano-sized drug delivery systems, providing prolonged drug release due to its low solubility in water. In addition, thanks to its mucoadhesive properties, it can prolong contact time with various mucosal structures in the body. Last but not least, the positive charge of chitosan allows it to interact with negatively charged drug structures, such as nucleic acids, making it a promising carrier in gene-based therapies, increasing the stability of various nucleic acids and protecting them from rapid elimination from the bloodstream [92].

Due to its positive charge, chitosan can interact with the negatively charged liposome surface, significantly increasing their colloidal stability, but allowing limited control over the drug release process due to its solubility in acidic pH. Nevertheless, chitosan is one of the most widely used polysaccharides for surface modification of liposomes [93].

Due to its mucoadhesive properties, chitosan is used to prolong the retention time of liposomes on various mucosal surfaces and is widely used in pulmonary drug delivery [94,95]. Various studies have reported the positive effect of chitosan coating on liposomes, significantly prolonging retention on respiratory tract structures compared to pure substances and unmodified liposomes, but it should be noted that sometimes, with prolonged retention on the mucous layer, there is a possibility of a decrease in the degree of penetration of drug molecules through it [94]. A similar effect is observed by Kannavou et al., 2023, who found that nanoemulsions of the synthetic neurosteroid BNN27 have better in vitro penetration through a cell monolayer simulating the blood–brain barrier, compared to chitosan-coated liposomes, probably due to their strong adhesion to cells [96]. However, when administered nasally in animal models, the scientists observed a higher concentration of the drug in chitosan-modified liposomes compared to unmodified liposomes.

There are also several studies on the effects of chitosan as a modifying agent in the oral administration of liposomes. However, it should be noted that it dissolves in the acidic pH of the stomach, releasing the liposomes and their cargo at this stage [97]. This requires modification of the structure of chitosan to reduce its solubility in the acidic pH of the stomach so that the structure can pass through the stomach unchanged. Various modified forms of chitosan with mannose [98] and gelatin [99] were prepared, which improve penetration through the mucous layer of the small intestine, which is a problem with unmodified forms of chitosan.

Due to its positive charge, chitosan can attach to the negatively charged cell walls of bacteria, making it a suitable agent for targeting liposomes in antimicrobial therapy. Thus, liposomes coated with chitosan and loaded with various natural antimicrobial agents have been developed, and scientists have observed an increase in chemical stability and improvement in the pharmacokinetic characteristics of the compounds after their inclusion in a chitosan-modified liposome structure [100,101].

4.2. Alginate

Alginates are water-soluble polysaccharides isolated from various types of brown algae and some types of bacteria. They are unbranched copolymers composed of β-(1–4)-D-mannuronic (M-block) and α-(1–4)-L-guluronic residues (G-block), which can be linked together in different sequences (MM, GG, MG). A characteristic feature of alginates is that they form water-soluble salts with monovalent metals, while with divalent metals they cross-link to form hydrogel systems [102].

Due to the properties of the hydrogel systems they form, alginates are widely used as carriers for various micro- and nanoscale drug delivery systems, such as microspheres, microcapsules, micelles, micro- and nanogels, etc. In addition, their hydrogels are characterized by a pronounced wound-healing effect, which makes them widely used components in various hydrogel drug forms for dermal and ophthalmic application [103].

Due to their negative charge, alginates interact easily with positively charged liposomes, allowing the formation of a dense coating on their surface, especially in cases in which liposomes are adapted for oral administration. Many scientists report significantly reduced drug release under gastric pH conditions, protecting sensitive substances such as peptides from acid degradation and ensuring their complete delivery to the small intestine [104,105].

The negative charge of sodium alginate allows the formation of multiple layers using the “layer-by-layer” method, applied in combination with other positively charged modifying substances such as chitosan [106,107,108] or proteins [109] thereby improving their characteristics such as their degradation in acidic pH and improving the delivery of the structures to the intestine, while also increasing the loading efficiency of the substances and improving their pharmacokinetics [107].

4.3. Dextran

Dextran is an exopolysaccharide produced by lactic acid bacteria and is a product of their enzymatic processing of sucrose. It is composed of a linear chain of D-glucose residues linked together by α-(1–6) bonds. It may also contain branched chains of D-glucose linked by α-(1–4), α-(1–3), and α-(1–2) bonds. It is characterized by good biocompatibility and non-immunogenicity. Low-molecular-weight and unbranched dextrans are usually highly soluble in water, while as the molecular weight and degree of chain branching increase, processes of water absorption and retention begin to predominate [110].

Unlike other polysaccharides, dextran is not processed by amylase but is rather by dextranase in the lumen of the large intestine, liver, and kidneys. This makes dextran a suitable carrier for drugs that are sensitive to degradation in the stomach and small intestine or for targeted delivery of therapeutics to the large intestine [111]. In addition, the structure of dextran allows for easy modification to optimize the pharmacokinetic profile of the developed structure and target it to the desired areas of the body. This is one of the reasons for the widespread use of dextran and its modified forms such as esters, ethers, dialdehydes, etc. [112].

It has been demonstrated that the modified forms of dextran that are widely used as means for surface modification of liposomes, mainly due to its high resistance to the conditions of the gastrointestinal tract and the creation of pH-dependent release [113], as well as its ability to increase the colloidal stability of liposomes [114].

In addition, Letourneur et al., 2000, developed a modified form of dextran with various functional groups (carboxymethyl, benzylamine, sulfate/sulfonate, and amino groups) [115]. They reported that liposomes coated with functionalized dextran attached to smooth muscle cells from rat aorta to a much greater extent than their uncoated counterparts.

4.4. Pectin

Pectin is a heteropolysaccharide found in the skins of the fruits of some higher plants and is one of the components of the plant cell wall. It has a complex structure consisting of linearly linked residues of α-(1–4)-D-galacturonic acid esterified with methyl or acetyl residues (homogalacturonan). In addition, it contains various regions composed of branched polysaccharide chains called xylogalacturonan, rhamnogalacturonan I, and rhamnogalacturonan II, depending on the residues that compose them. Xylogalacturonane chains are composed of α-(1–4)-D-galacturonic residues esterified with β-D-xylose at the C3 atom to varying degrees. Rhamnogalacturonan I chains are composed of repeating α-(1–4)-L-galacturonic and α-(1–2)-L-rhamnopyranose residues. The rhamnose in the chains can be linked, to varying degrees, to polysaccharides such as arabinan, galactan, or arabinogalactan. Rhamnogalacturonan II chains are one of the most complex glycan structures known, consisting of a basic homogalacturonan backbone linked to at least twelve different monosaccharide residues [116].

Pectins can be divided into two main groups, depending on the degree of esterification of their glucuronic residues (degree of esterification, DE), considering those with a low degree of esterification (DE < 50%) and those with a high degree of esterification (DE > 50%). Pectin can form gels under various conditions, and the characteristics of the gels it forms depend largely on the degree of esterification of the pectin [117].

A characteristic feature of pectin is that it passes through the stomach relatively unchanged and is broken down by enzymes called “pectinases,” which are produced by bacteria in the large intestine. This makes it a suitable carrier for drug delivery systems targeting the large intestine [118].

Pectin is a widely used carrier for various drug forms such as gels, microparticles, nanoparticles, etc., finding application in the delivery of substances for diseases such as diabetes, inflammatory diseases of the gastrointestinal tract, infectious diseases, etc. Of particular interest is the role of pectin in antitumor therapy, as there is strong evidence that its mechanism of action is related to the inhibition of galectin-3 and the stimulation of apoptosis through the activation of the caspase-3/PARP reaction [119].

Due to its polyanionic nature, pectin allows electrostatic interaction with the positively charged surface of cationic liposomes. Its ability to pass unchanged through the segments of the gastrointestinal tract is often exploited, as is its antitumor effect and synergistic antitumor effect in combination with certain cytostatics [120]. In addition to the electrostatic mechanism of interaction, Ferreira et al., 2025, demonstrated that pectin can interact with the liposome surface and through the formation of hydrogen and hydrophobic bonds with the phospholipid membrane of liposomes, leading to its compression and the formation of stable hybrid structures, which allows a modification of liposomes of different nature [121].

In addition to this effect, many scientists report that coating liposomes with pectin significantly increases the stability of the liposome membrane [122], an increase in the loading efficiency of the drug substance, and an increase in stability during the passage of the vesicles through the gastrointestinal tract [123,124].

Last but not least, it should be noted that, although to a significantly lesser extent than polymers such as chitosan, pectin also exhibits mucoadhesive properties. For example, in combination with chitosan, Xian et al., 2021, developed modified liposomes that exhibit a very high degree of adhesion to the intestinal mucosa compared to unmodified liposomes, while significantly increasing the anti-inflammatory effect of celastrol and reducing its release in the upper gastrointestinal tract [125].

4.5. Fucoidan

Fucoidan is a sulfated polysaccharide that is mainly isolated from various types of seaweed. Its main chain is made up of fucose residues that can be linked together by α-(1–2) or α-(1–3) bonds. Other sugars such as galactose, mannose, xylose, glucuronic acid, etc., can also be linked to it, with substitution most often occurring at the C2 or C4 position of the L-fucopyranosyl residues [126].

Fucoidan is characterized by biodegradability and good biocompatibility, and has multiple therapeutic effects, one being its antitumor activity. This effect is achieved through fucoidan’s cytostatic activity, immunomodulatory and pro-apoptotic functions. In addition, it also exhibits anti-metastatic activity by suppressing the dissemination of cells from the primary tumor to distant sites. Last but not least, fucoidan is also a ligand for P-selectin, and this function is associated with an increase in the intracellular uptake of chemotherapeutic agents and a decrease in their efflux outside the cell, thus overcoming the chemoresistance of many tumors [127].

Thanks to these characteristics, fucoidan is widely used as a carrier in various types of drug formulations, especially those used in regenerative therapy, due to its ability to swell and retain water in its structure. In addition, fucoidan can also be a carrier for various porous materials where the degree of porosity needs to be controlled [128].

Fucoidan is also widely used as a carrier in micro- and nano-sized drug delivery systems. In addition to its therapeutic effects, its characteristic pH-sensitive degradation is also utilized, as it can impart selectivity to the developed structures and direct the drug to the desired regions [129].

Due to its anionic nature, fucoidan allows polyelectrolyte interactions with structures with opposite charges, such as the surface of cationic liposomes. The main functions of fucoidan as a polysaccharide that can be used to modify the surface of liposomes are related to its antitumor activity and its ability to bind to P-selectin, which is used to direct liposomes carrying chemotherapeutic agents to specific tumors [130]. In addition, a number of scientists have demonstrated that modifying liposomes with fucoidan, either alone or in combination with other modifying agents, significantly increases their stability at different pH ranges, thereby drastically reducing premature drug release [131], while at the same time significantly increasing the colloidal and chemical stability of liposomes [132].

4.6. Beta-Glucan

Beta-glucans are a large group of polysaccharides composed of D-glucose monomers, and in general, their structure is a linear chain composed of D-glucopyranosyl units linked by β-(1–3), β-(1–4), or β-(1–6) bonds. They are widely found in many organisms such as bacteria, fungi, both lower and higher, algae, cereals, etc. In addition to their origin and molecular weight, β-glucans can also be classified based on the structure of their chains, as their therapeutic properties depend on these characteristics [133].

Beta-glucans are classified as dietary fiber and are characterized by a pronounced prebiotic effect, reduce the amount of free oxygen radicals, and have the ability to capture excess cholesterol, with these actions mainly observed in beta-glucans obtained from cereals [134]. Beta-glucans of fungal origin, such as lentinan, pleuran, etc., have a very significant therapeutic effect. They are characterized by a strong immunomodulatory effect and are known to interact specifically with receptors such as dectin-1, complement receptor 3 (CR3), or toll-like receptor 2, which are directly involved in the macrophage activation [135]. In addition, they promote the expression of tumor antigens, and, through T-cell activation, beta-glucans also restore the action of NK cells, which are normally suppressed in the tumor microenvironment, through a CR3 receptor mechanism. Thus, by reducing suppressive factors and inducing apoptotic processes, they also exert their antitumor effect [136].

In pharmaceutical practice, beta-glucans are widely used due to their therapeutic and technological characteristics. In addition to being carriers and adjuvants for various drugs in antitumor therapy, they are often used in the development of various types of vaccines, solely because of their immunomodulatory potential [137].

Although less common, various beta-glucans are also used as surface-modifying agents for liposomes. One of the main reasons for their use is their immunomodulatory effect, with a synergistic effect usually reported and beta-glucans potentiating the action of the drug substance [138]. In addition, they have been reported to potentiate other therapeutic effects, such as the antioxidant effect of certain substances [139].

However, when using beta-glucans, certain characteristics must be taken into account, such as the fact that unmodified beta-glucans are usually anionic in nature, which makes them more suitable for deposition on cationic liposomes, whereas with neutral or anionic ones, practically no coating is formed [140,141]. Other factors that directly influence the quality of beta-glucan coatings are their molecular weight and chain structure. High-molecular-weight beta-glucans, such as those from yeast, with very long chain branches are not suitable because they can form an uneven coating, disrupting the geometric shape of the vesicles. On the other hand, beta-glucans with very low molecular weight cannot form a dense coating around liposomes due to their short chains and low molecular weight. Excessive branching in high-molecular-weight β-glucans can lead to steric hindrance and heterogeneous surface adsorption, whereas moderately branched β-glucans favor uniform coating and improved colloidal stability. The most suitable are beta-glucans with an average molecular weight of Mw ≥ 30 kDa, whose chains have short branches of mono- or oligosaccharides [141].

4.7. Inulin

Inulin is a linear polysaccharide composed of D-fructofuranose units linked by β-(1–2) bonds, with a glucose residue linked by an α-(1–2) bond at the end of the chain. It is mainly obtained from various plant sources of the Liliaceae, Amaryllidaceae, and Asteraceae. Due to the β-configuration of its chain, inulin is resistant to the enzymes of the human gastrointestinal tract and is broken down by enzymes from bacteria in the intestine, also acting as a prebiotic [142].

Due to the peculiarities of its breakdown, inulin exerts its main effect locally in the intestine. In addition to its probiotic effect on the intestinal microbiome, it and some of its metabolites are known to have a pronounced anti-inflammatory effect, which results from the stimulation of the transcription of certain anti-inflammatory interleukins, IL-4 and IL-10, as well as the stimulation and regulation of immune cells in the intestine, improving the metabolic activity of T cells [143]. In addition, inulin has also been shown to increase intestinal levels of glutathione peroxidase, superoxide dismutase, and catalase, thereby presenting strong antioxidant activity [144].

In pharmaceutical practice, inulin is widely used as a carrier for various drug delivery systems such as hydrogels, micelles, micro- and nanoparticles, solid dispersions, etc. The main advantage of inulin is its degradation mechanism, which makes it suitable for directing drug delivery to the large intestine. On the other hand, high-molecular-weight inulins are characterized by lower water solubility, which makes them a good choice for the development of delayed and controlled drug release systems. One of the main applications of inulin as a surface modifying agent of liposomes is the targeted delivery of vesicles to the large intestine [145], while also significantly increasing the physical and chemical stability of liposomes, protecting them from degradation in the gastrointestinal tract [145,146]. Although inulin itself has a certain antioxidant effect, scientists report that in the development of inulin-modified liposomes, a significant decrease in the in vitro antioxidant activity of some substances is observed compared to that of unmodified liposomes [146,147].

4.8. Carrageenan

Carrageenans are a group of sulfated polysaccharides, usually isolated from the extracellular matrix of red algae. Their structure consists of D-galactose residues with alternating α-(1–3) and β-(1–4) bonds, and they also contain between 15% and 40% ester-sulfate bonds. Carrageenans are classified according to the number and the position of their sulfate groups, with some of the most important ones for pharmaceutical practice being kappa (κ-), iota (ι-) and lambda (λ-) carrageenan [148].

Carrageenans have been found to have a strong antitumor effect, with different mechanisms of action known for different carrageenans. For example, some act by influencing the Wnt/β-catenin signaling pathway (ι- and λ-carrageenan), influencing the TLR4 signaling pathway and stimulating the activity of NK cells, macrophages, the T/B-cell response (λ-carrageenan), stimulating apoptosis by activating caspase-3, antioxidant effect, etc., but it should be noted that the mechanisms of antitumor effect vary significantly depending on the molecular weight and type of carrageenan [149].

Carrageenans find relatively limited use as agents for surface modification of liposomes. However, their anionic nature allows deposition and electrostatic interaction with the positively charged liposome surface. It has been found that modifying the liposome structure with κ-carrageenan significantly increases the in vitro antioxidant activity of quercetin compared to modifications with pectin and trehalose, as well as compared to unmodified vesicles [150].

4.9. Cellulose

Cellulose is a linear polysaccharide composed of β-(1–4) linked glucose units. The structure of cellulose consists of multiple linear chains of D-glucose linked together by H-bonds formed by the hydroxyl groups at the C2, C3, and mainly C6 positions, forming the crystal structure of cellulose. It is precisely because of the strong inter- and intramolecular hydrogen bonds and van der Waals bonds that cellulose is characterized by low solubility in water, but on the other hand, by very good biocompatibility and biodegradability [151].

Due to its low solubility in water, native cellulose has relatively limited application in the biomedical field. Cellulose derivatives obtained through reactions such as esterification, etherification, oxidation, cross-linking, etc., are much more widely used, as they introduce various functional groups into the cellulose structure, which significantly improves its characteristics. Some of the most widely used cellulose derivatives are, for example, ethyl cellulose (EC), methyl cellulose (MC), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), and carboxymethyl cellulose (CMC) (Figure 6) [152].

Cellulose and its derivatives are widely used in pharmaceutical practice as carriers for various micro- and nanocomposite systems, emulsifiers, carriers for hydrogels, transdermal patches, implants, etc. This is due to the easy availability of cellulose and its relatively easy modification, which can be used to impart different characteristics to its derivatives [151].

Native cellulose is used to a significantly lesser extent as a surface modifier for liposomes, but its derivatives are much more widely used. Some of the main reasons for modification are to increase the colloidal stability of liposomes and reduce the amount of drug released during storage [153]. In addition, derivatives that have the ability to form a hydrogel layer around liposomes serve to control the drug release process after liposome administration [154]. Derivatives of bacterial origin, for example, can provide high stability of liposomes in the gastrointestinal tract, making them a suitable coating for oral delivery of liposomes. Another advantage of cellulose derivatives is that they allow both electrostatic interactions with liposomes [155] and interactions independent of the charge of the liposomes, such as hydrophobic and H-bonds [153].

4.10. Natural Gums

Gums are natural polysaccharides that are widely used in the pharmaceutical industry as viscosity-enhancing and gelling agents, emulsifiers, etc., due to their easy availability and low cost. In addition, gums are also used as carriers for various drug forms such as substrates, films, various composite systems, as well as for micro- and nano-sized drug delivery systems [156].

Xanthan gum is an exopolysaccharide obtained by aerobic fermentation of sugars by bacteria of the genus Xanthomonas. Structurally, it is a heteropolysaccharide whose main chain is composed of D-glucose units linked by β-(1–4) bonds. The side chains of xanthan gum are composed of β-D-mannose-(1–4)-β-D-glucuronic acid-(1–2)-α-D-mannose linked to C3 of the glucose residues of the main chain [157].

Xanthan gum is characterized by very high resistance to pH changes, both in the acidic and alkaline ranges. In addition, it has significantly higher thermal sensitivity compared to other hydrophilic hydrocolloids, maintaining its rheological characteristics regardless of temperature changes. Due to these advantages, it is widely used in pharmacy as a matrix for controlled release, alone or in combination with other polymers, as well as for oral delivery of proteins and peptides due to its high stability in the gastrointestinal tract [158]. The use of xanthan gum as a surface modifier of liposomes is again related to its high stability. Scientists report that coating liposomes with xanthan gum significantly increases their thermal and pH stability, while also protecting phospholipids and the drug substance from oxidative degradation [159,160].

Gum arabic is a widely used polysaccharide in the pharmaceutical industry due to its high-water solubility, biocompatibility, and biodegradability, as well as its good emulsifying properties. It is mainly composed of D-galactopyranosyl residues linked by β-(1–3) bonds. The main chain may have side chains consisting of two to five β-(1–3)-D-galactopyranosyl residues linked by β-(1–6) bonds [161]. Although it is widely used as a carrier for various medicinal substances for oral and dermal application, etc. [162]. Gum arabic has relatively limited application as a means of surface modification of liposomes. Due to its negative charge, it allows electrostatic interaction with cationic liposomes, increasing their physical and thermal stability. In addition, Cheng et al., 2024, report that modification of liposomes with gum arabic significantly improves the lipid-reducing effect in cells, which is probably due to improved penetration of the structures into the cells [160].

Guar gum is a heterogeneous polysaccharide from the galactomannan group. The structure of guar gum contains a main chain composed of β-(1–4)-D-mannose residues to which α-(1–6)-D-galactose side chains are attached. It is widely used in pharmacy due to its easy availability, biodegradability, low toxicity, and the good characteristics of the gels it forms. It swells in water, forming a colloidal dispersion, and when the temperature rises and the pH of the medium decreases, its solubility in water increases [163].

Guar gum is widely used in the development of various dosage forms as it has optimal binding characteristics, can be used as an emulsifier or suspending agent, as well as a carrier for various controlled-release drug delivery systems. It is important to note that modified forms of guar gum are more widely used due to some of its disadvantages, such as low microbiological stability, the distinctive characteristics of the dissolution process, and the nature of the dispersions it forms [164]. Guar gum and its modified forms are also used as means for surface modification of liposomes, as one of the most significant advantages of guar gum coatings is their high physical stability. It has been reported that modifying the liposome surface with guar gum significantly increases thermal stability, improves the chemical stability of liposomes, and increases their stability in different pH ranges [160,165]. Some modified forms of guar gum, such as cationic guar gum, have been reported to significantly reduce the fluidity of the liposome membrane and increase the storage stability of liposomes when electrostatically coated [166].

To provide a concise overview of the polysaccharides discussed in this section, their surface modification strategies, and representative biomedical applications, a summary table is presented below (

Table 1. Polysaccharides used for liposomal surface functionalization: modification strategies and representative applications.

Polysaccharide	Modification Method	Active Substance	Potential Application	Reference
Pectin/Chitosan	Layer-by-layer technique	Celastrol	Colon-targeted drug delivery	[125]
Pectin	Single layer deposition technique	Metronidazole	Local treatment of vaginal infections	[167]
Pectin	Single layer deposition technique	Vitamin D3/Vitamin B12	To increase the colloidal stability of liposomes	[121]
Pectin DE > 55%	Single layer deposition technique	Cistanche phenylethanoid glycosides	To study the influence of pectin coating on the entrapment efficiency, stability under GIT conditions, influence on the release process, and in vitro bioavailability	[124]
Pectin DE > 74%/Soy-β-conglycinin	Layer-by-layer technique	Morin	To investigate the influence of the coating on the membrane structure under storage conditions and under GIT conditions, as well as the influence of the coating on the antioxidant activity of the active ingredient.	[122]
Pectin DE 70% > 75%	Single layer deposition technique	Nisin	To examine the influence of the coating on stability, its effect on the release process of the active ingredient, as well as the influence on the antimicrobial effect of Nisin.	[123]
Pectin DE < 26%	Single layer deposition technique	Bufalin	To investigate the influence of the coating on the stability of liposomes during storage, the mucoadhesion of the resulting structure, and the antitumor effect of the active ingredient.	[120]
Folic acid/Cysteine/Thiolated Chitosan	Single layer deposition technique	Doxorubicin	To create a dual-targeting system (folate receptor + redox-responsive release) for melanoma cancer therapy.	[95]
Mannosylated Chitosan	Single layer deposition technique	Andrographolide	To target liver mannose receptors and enhance oral bioavailability/stability for hepatitis treatment.	[98]
Chitosan	Single layer deposition technique	BNN27 (Synthetic microneurotrophin	To compare liposomes vs. nanoemulsions for nose-to-brain delivery and enhance mucoadhesion.	[96]
Chitosan	Single layer deposition technique	Moringin	To improve the stability of the volatile active compound and enhance its antibacterial mechanism against S. aureus.	[100]
Chitosan	Single layer deposition technique	Clove Essential Oil	To improve thermal stability and antioxidant activity of the active ingredient.	[168]
Chitosan and Gelatin	Layer-by-layer technique	Curcumin + E. coli Nissle 1917 (Probiotic)	To protect probiotics in the GI tract and achieve synergistic therapy for ulcerative colitis.	[99]
Catechol-modified Chitosan	Single layer deposition technique	Resveratrol + Carnosine	To enhance skin adhesion and penetration for synergistic anti-aging effects (anti-oxidation/anti-glycation).	[169]
Chitosan	Encapsulation by polysaccharide cross-linking	Carissa spinarum extract	To enhance bioavailability and antibacterial potency against Klebsiella pneumoniae.	[101]
Chitosan/Sodium Alginate	Layer-by-layer technique	Hydroxy-α-Sanshool	To enhance oral bioavailability, improve stability (pH sensitivity), and achieve sustained release of the drug.	[106]
Alginate (reinforced with plant proteins)	Encapsulation by polysaccharide cross-linking	Glechoma hederacea L. extract	To formulate delivery systems for candies, reduce leakage, and provide prolonged controlled release during digestion.	[109]
Chitosan, Sodium Alginate, Pectin, Inulin	Single layer deposition technique	Cyanidin-3-O-glucoside	To improve physicochemical stability, inhibit degradation in the GI tract, and prolong release.	[105]
Sodium Alginate/Chitosan	Layer-by-layer technique	Folic acid and Vitamin E	To co-encapsulate hydrophilic and hydrophobic nutrients, improve stability, and enhance bioavailability/release in the GI tract.	[108]
Sodium Alginate	Single layer deposition technique	DPP-IV inhibitory collagen peptides	To protect the peptides from gastric inactivation, improve stability, and enhance intestinal absorption/bioavailability.	[104]
Oat-beta-glucan	Encapsulation by polysaccharide cross-linking	Beta-carotene	To investigate the effect of beta-glucan coating on stability, controlled release, bioaccessibility, and intestinal absorption of the lipophilic active agent.	[139]
Beta-glucan from Pleurotus eryngii	Single layer deposition technique	-	To investigate the ability of different P. eryngii glucan fractions to coat liposomes and activate the dectin-1b receptor.	[140]
Beta-glucan from Lactarius spp.	Single layer deposition technique	-	To determine the chemical structure of Lactarius glucans and correlate it with their ability to coat liposomes and improve stability.	[141]
pH-responsive beta-glucan derivative	Surface modification via hydrophobic anchoring	Ovalbumin	To evaluate the effect of liposome size on the induction of cellular and humoral immune responses for cancer immunotherapy.	[138]
K-carrageenan	Single layer deposition technique	Quercetin	To mitigate the intense bitterness of quercetin, improve stability, and facilitate its application in functional foods.	[150]
Fucoidan/Chitosan	Layer-by-layer technique	Rutin	To enhance the physicochemical stability and oral bioavailability of the hydrophobic flavonoid rutin.	[131]
Fucoidan	Single layer deposition technique	Gemcitabine and Pin1 siRNA	To co-deliver a chemotherapeutic agent and gene therapy (siRNA) for a synergistic effect against pancreatic cancer.	[130]
Fucoidan/Chitosan	Layer-by-layer technique	Catechin and Juglone	To simultaneously encapsulate hydrophilic and hydrophobic actives, improving their stability and oral bioavailability.	[132]
Hyaluronic Acid/Inulin	Chemical conjugation	5-Fluorouracil Metformin Chlorin e6	To develop an oral colon-targeted delivery system for synergistic photo-chemotherapy, utilizing Inulin for colon targeting and HA for CD44 receptor targeting on tumor cells.	[145]
Chitosan/Lactose/Inulin	Layer-by-layer technique	Quercetin	To compare how different polysaccharide coatings (charged vs. neutral, different molecular weights) affect the microstructure and radical scavenging (antioxidant) activity of the liposomes.	[147]
Inulin	Single layer deposition technique	Cinnamaldehyde	To improve the physical stability, thermal stability, and antioxidant activity of the volatile essential oil component by modifying the liposome surface.	[146]
Guar Gum	Single layer deposition technique	Cyanidin-3-O-glucoside	To improve physicochemical stability, cellular uptake, and controlled release of the anthocyanin using a plant-derived fiber coating.	[165]
Xanthan Gum	Single layer deposition technique	Ascorbic Acid	To significantly improve the encapsulation efficiency and retention of Vitamin C in simulated gastric/intestinal fluids.	[159]
Cationic Guar Gum	Single layer deposition technique	Curcumin	To compare the stabilizing effects of native vs. cationically modified guar gum, finding that cationic guar gum offered superior membrane stabilization.	[166]
Diethylaminoethyl-Dextran	Single layer deposition technique	Curcumin	To stabilize soy lecithin liposomes, prevent aggregation, and enhance the encapsulation efficiency of the hydrophobic drug.	[114]
Hydrophobized Carboxymethyl Dextran	Hydrophobic anchoring	Doxorubicin	To reduce plasma protein adsorption (stealth properties), provide ligand attachment sites, and achieve sustained release.	[113]
Hydrophobically modified Hydroxyethyl cellulose	Hydrophobic anchoring	5(6)-carboxyfluorescein	To investigate the influence of hydrophobic chain length and degree of modification on stability and release properties of uncharged liposomes.	[153]
Sodium carboxymethyl cellulose	Single layer deposition technique	Cinnamaldehyde	To improve the stability and salt tolerance of liposomes in high ionic strength environments	[170]
Bacterial Cellulose Nanofibers	Single layer deposition technique	Paclitaxel	To develop a sustained-release oral delivery system with enhanced stability in gastrointestinal fluids for cancer treatment.	[155]

).

5. Conclusions

Polysaccharide-modified liposomes represent a significant advancement in nanomedicine, addressing the critical limitations of conventional vesicular systems. The primary strength of this approach lies in its ability to enhance colloidal stability while providing “stealth” properties that prolong systemic circulation without the immunogenic risks associated with PEGylation (the “Accelerated Blood Clearance” phenomenon). In addition, the inherent biodiversity of polysaccharides provides unique functional benefits. For example, hyaluronic acid facilitates the active targeting of tumors that overexpress CD44, while mucoadhesive polymers, such as chitosan and alginate, enhance retention at mucosal surfaces, thereby improving local bioavailability.

However, the translation of these systems is hindered by fundamental limitations (weaknesses) concerning formulation complexity and reproducibility. The effectiveness of surface modification is significantly influenced by parameters such as molecular weight and charge density. For instance, high-molecular-weight beta-glucans can lead to steric hindrance and the formation of uneven coatings, while unmodified chitosan may undergo premature dissolution in gastric environments. Furthermore, while non-covalent deposition techniques exhibit a high degree of versatility, they are susceptible to instability under varying physiological conditions in comparison to covalent conjugation.

There are considerable opportunities in the future to expand the clinical utility of these carriers, particularly in oral and site-specific delivery. The capacity of polymers such as pectin and inulin to withstand gastric digestion while undergoing specific degradation within the colon introduces novel prospects for targeted treatment of gastrointestinal diseases. Furthermore, the incorporation of stimuli-responsive elements, such as pH-sensitive release in tumor microenvironments, represents a promising approach for the development of “smart” theragnostic systems.

To achieve this goal, the field must address external threats, primarily the challenge of scalability and biological barriers. While mucoadhesion is advantageous, it may generate a paradox in which strong adhesion traps carriers within the mucus layer, thereby limiting deep tissue penetration, as reported in certain nose-to-brain delivery studies. Consequently, future research must prioritize optimization of the physicochemical balance of polysaccharide coatings to ensure manufacturing robustness and to overcome biological hurdles for successful clinical translation.