Liposomes as Smart Drug Delivery Vehicles: Advances, Applications, And Future Prospects

Abstract

Liposomes are spherical vesicles composed of one or more phospholipid bilayers that have emerged as versatile and biocompatible carriers for drug delivery. Their unique structural characteristics allow encapsulation of both hydrophilic and lipophilic drugs, enhancing solubility, stability, and targeted delivery. Over the past few decades, liposomal formulations have demonstrated significant potential in improving the therapeutic efficacy of various drugs while minimizing toxicity. This review highlights the structural and compositional aspects of liposomes, preparation methods, mechanisms of drug delivery, and their applications in diverse therapeutic areas including cancer, infectious diseases, and gene therapy. Emphasis is also placed on advanced liposomal technologies, their role in combination therapies, regulatory challenges, and clinical translation. As research advances, liposomes continue to play a pivotal role in modern drug delivery systems, offering promising avenues for precision medicine and nanotherapeutics.

Keywords

Introduction

Fig No 1: Structure of Liposome

Depending on their structural characteristics, liposomes can be categorized into different types:

• Unilamellar vesicles (ULVs): Consist of a single phospholipid bilayer. These are further classified into small unilamellar vesicles (SUVs, 20–100 nm) and large unilamellar vesicles (LUVs, >100 nm).
• Multilamellar vesicles (MLVs): Contain multiple concentric phospholipid bilayers, resembling an onion-like structure, typically ranging from 0.1 to 10 μm in diameter
• Multivesicular vesicles (MVVs): Consist of multiple non-concentric vesicles enclosed within a larger liposome.

Certain surface alterations can be used to further customize the liposomes' composition. For example, polyethylene glycol (PEG) chains are attached to the liposomal surface during PEGylation, giving the liposome a "stealth" quality that reduces identification and removal by the mononuclear phagocyte system (MPS). It is possible to conjugate additional surface ligands, including aptamers, peptides, or antibodies, to enable active targeting to particular cells or organs. Overall, liposomes are particularly adaptable carriers due to their structural and compositional flexibility, which allows for the creation of unique delivery systems for a range of medical and diagnostic applications. ^[8]

5. Classification of Liposomes

Liposomes can be classified based on various parameters such as size, number of bilayers (lamellarity), method of preparation, and their composition. Understanding the classification of liposomes is essential for designing suitable formulations for specific therapeutic applications ^[9].

• Based on Size and Lamellarity

Liposomes are broadly divided into three major categories according to their size and lamellarity:

• Small Unilamellar Vesicles (SUVs):
  These liposomes have a single phospholipid bilayer and a size range typically between 20 to 100 nm. SUVs are often prepared by sonication or extrusion methods and are widely used for drug delivery owing to their small size and improved circulation profiles.
• Large Unilamellar Vesicles (LUVs):
  LUVs possess a single lipid bilayer but have a larger diameter, usually ranging from 100 to 1000 nm. They offer a larger internal aqueous volume, making them suitable for the encapsulation of hydrophilic drugs.
• Multilamellar Vesicles (MLVs):
  MLVs consist of multiple concentric phospholipid bilayers resembling an onion-like structure. Their size can vary widely from 100 nm to several micrometers. MLVs are relatively simple to prepare and are commonly used in basic research and preliminary drug delivery studies ^[10].

• Based on Method of Preparation

The method employed for liposome preparation can also define their structural characteristics:

• Conventional Liposomes:

Prepared by simple techniques such as thin-film hydration, leading to the formation of MLVs. These liposomes may require further processing like sonication to reduce size.

• Stealth Liposomes (PEGylated Liposomes):
  Modified with polyethylene glycol (PEG) chains on their surface, these liposomes evade detection by the mononuclear phagocyte system (MPS), thereby achieving prolonged circulation time
• Targeted Liposomes:

These liposomes are functionalized with ligands (antibodies, peptides, or small molecules) to specifically bind to target cells or tissues, improving therapeutic efficacy and reducing systemic side effects. ^[11].

• Based on Composition

• Conventional Phospholipid Liposomes:
  Comprised solely of natural or synthetic phospholipids and cholesterol.
• Cationic Liposomes:

Incorporating positively charged lipids to facilitate the encapsulation of negatively charged drugs, nucleic acids, or genes for gene delivery applications.

• Stimuli-Responsive Liposomes:

Designed to release their contents in response to specific stimuli such as pH, temperature, or enzymatic activity, providing controlled and targeted drug release. ^[12]

5. Methods of Liposome Preparation

The preparation method greatly influences the size, lamellarity, encapsulation efficiency, and stability of liposomes. Various techniques have been developed to produce liposomes tailored to specific therapeutic needs. The most commonly used methods are described below.

• Thin Film Hydration Method (Bangham Method)

This is the most conventional and popular method for making liposomes. A chloroform or chloroform-methanol mixture is usually used as the organic solvent to dissolve phospholipids and cholesterol. After that, the solvent is evaporated at lower pressure, leaving a thin layer of lipids on the flask's round-bottom wall. Multilamellar vesicles (MLVs) are then spontaneously formed when this film is hydrated with an aqueous solution while being shaken. Smaller unilamellar vesicles (SUVs) are produced by further processing techniques like extrusion or sonication.

• Reverse Phase Evaporation Method

Using this technique, a mixture of phospholipids mixed in an organic phase and an aqueous phase is sonicated to create a water-in-oil emulsion. The emulsion collapses and liposomes are created when the organic solvent is removed at a lower pressure. For hydrophilic medications, this technique usually produces large unilamellar vesicles (LUVs) with high encapsulation efficiencies ^[13].

• Solvent Injection Methods

Phospholipids mixed in an organic solvent that dissolves in water, like ethanol, are injected quickly into an aqueous phase in solvent injection techniques, which causes tiny liposomes to form instantly. Common versions include ether injection and ethanol injection. Although these techniques are straightforward and scalable, they frequently call for the elimination of leftover organic solvents.

• Sonication Method

Sonication is a mechanical method used to reduce the size of liposomes. By applying ultrasonic energy, multilamellar vesicles (MLVs) can be disrupted and rearranged into small unilamellar vesicles (SUVs). However, this method may cause degradation of sensitive compounds due to the generation of heat and free radicals^{. [14]}

• Extrusion Method

In the extrusion method, liposomes are forced through polycarbonate membranes with defined pore sizes using a high-pressure extruder. This process results in liposomes of uniform size distribution, typically in the nanometer range Extrusion is commonly combined with thin film hydration to achieve better control over liposome size. ^[15]

• Microfluidic Method

Recent advancements include the use of microfluidic devices for the continuous and reproducible production of liposomes. By precisely controlling the flow rates of lipid-containing organic phases and aqueous phases, uniform liposomes with narrow size distributions can be produced. Microfluidic methods offer high reproducibility, scalability, and suitability for industrial production. ^[16]

5. Characterization of Liposomes

The comprehensive characterization of liposomes is a crucial step in ensuring their reproducibility, stability, efficacy, and safety. A detailed analysis of various physicochemical properties not only optimizes formulation development but also predicts there in vivo behavior. Several key parameters must be evaluated, as discussed below: ^[17]

• Particle Size and Size Distribution

Particle size significantly influences pharmacokinetics, biodistribution, and drug release profiles of liposomes. Liposomes intended for systemic delivery typically range from 50 to 200 nm to ensure prolonged circulation, reduced clearance by the mononuclear phagocyte system (MPS), and enhanced tumor accumulation through the enhanced permeability and retention (EPR) effect ^[18].

• Measurement Techniques:

Dynamic Light Scattering (DLS) remains the most widely used method to measure hydrodynamic diameter and polydispersity index (PDI), where a lower PDI (<0.2) indicates a more homogeneous population.
Nanoparticle Tracking Analysis (NTA) and Atomic Force Microscopy (AFM) provide complementary information regarding particle size and morphology ^[19].

• Impact:
  Particle size also affects cellular uptake mechanisms, with smaller vesicles favoring endocytic pathways.

• Zeta Potential

Zeta potential measures the surface charge of liposomes and predicts their colloidal stability. Highly charged particles (either positive or negative, generally > ±30 mV) exhibit strong repulsion forces, preventing aggregation and sedimentation.

• Measurement:
  Laser Doppler Electrophoresis is commonly used to determine the zeta potential values.
• Importance:
  Surface charge influences biodistribution, cellular uptake, and interactions with serum proteins ("protein corona" formation) ^[20].

• Morphology and Lamellarity

The morphology (shape, size, lamellarity) of liposomes impacts their drug encapsulation and release properties.

• Visualization Methods:

Transmission Electron Microscopy (TEM), Cryo-TEM, and Scanning Electron Microscopy (SEM) enable direct observation of vesicle shape and lamellar structures. Cryo-TEM is particularly useful because it preserves the native hydrated state of liposomes.

• Lamellarity:
  Techniques like Small Angle X-ray Scattering (SAXS) and freeze-fracture electron microscopy further confirm the number of bilayers. ^[21]

• Encapsulation Efficiency (EE) and Drug Loading

Encapsulation efficiency represents the percentage of drug incorporated into liposomes relative to the amount initially used.

• Quantification Methods:

Free drug is separated using ultracentrifugation, gel filtration, or dialysis, and then quantified using HPLC, UV-Visible spectroscopy, or fluorimetry

• Loading Capacity:

This defines the ratio of drug to total lipid content, affecting scalability and therapeutic dosing^{. [22]}

• Phase Transition Temperature (Tm)

The phase transition temperature (Tm) is the point at which the lipid bilayer switches from a gel to a fluid state.

• Measurement:
  Differential Scanning Calorimetry (DSC) determines the Tm, which varies depending on lipid composition (e.g., DPPC has a Tm ~41°C).
• Role:
  Tm influences membrane fluidity, drug retention, and sensitivity to external stimuli like temperature. ^[23]

• In Vitro Drug Release Studies

Understanding the drug release kinetics is vital for predicting therapeutic behavior.

• Methods:
  Dialysis bag diffusion, Franz diffusion cells, and microdialysis methods are used to monitor release profiles
• Release Models:

Release data are often fitted to kinetic models such as zero-order, first-order, Higuchi, or Korsmeyer-Peppas to elucidate underlying mechanisms

• Influence Factors:

Lipid composition, cholesterol content, vesicle size, and surface modification (e.g., PEGylation) can modulate release kinetics. ^[24]

5. Applications of Liposomes

Liposomes have revolutionized drug delivery by offering a versatile platform for encapsulating both hydrophilic and lipophilic molecules, enhancing drug solubility, stability, bioavailability, and targeted delivery. Their biocompatibility and ability to modify pharmacokinetic profiles have led to a wide range of clinical and industrial applications ^[25]. The major fields where liposomes have found significant utility are discussed below:

• Pharmaceutical Drug Delivery

Liposomes are extensively used to improve the therapeutic index of drugs by reducing systemic toxicity and enhancing drug accumulation at target sites.

• Cancer Therapy:

Liposome-based formulations such as Doxil® (liposomal doxorubicin) have been successfully developed to minimize cardiotoxicity while enhancing anti-tumor efficacy.

• Anti-fungal Agents:

AmBisome®, a liposomal formulation of amphotericin B, significantly reduces nephrotoxicity compared to conventional formulations while maintaining potent antifungal activity ^[26].

• Vaccine Delivery

Liposomes serve as potent adjuvants and delivery vehicles in vaccine formulations by enhancing antigen presentation and stimulating both humoral and cellular immune responses.

• Examples:
  Epaxal® (hepatitis A vaccine) and Inflexal® V (influenza vaccine) are liposome-based vaccines that demonstrate superior immunogenicity with improved safety profiles ^[27].

• Gene Delivery

Liposomes, especially cationic liposomes, are used for the delivery of genetic material (DNA, siRNA, mRNA) into cells. They protect nucleic acids from enzymatic degradation and facilitate cellular uptake via endocytosis.

• Applications:
  Gene therapy, mRNA vaccines (such as COVID-19 vaccines using lipid nanoparticles, which are a specialized form of liposomes), and RNA interference therapies heavily rely on liposomal carriers ^[28].

• Transdermal and Topical Delivery

Liposomes enhance drug penetration through the stratum corneum by disrupting lipid bilayers, allowing efficient transdermal or topical delivery.

• Examples:
  Liposome-based formulations are employed in dermatology for the treatment of psoriasis, acne, and fungal infections, and in cosmetics for delivering active ingredients into deeper skin layers ^[29].

• Diagnostic Imaging

Liposomes can be loaded with imaging agents (such as radionuclides, fluorophores, or MRI contrast agents) to act as diagnostic tools for cancer detection, cardiovascular diseases, and other pathologies.

• Advantages:
  Targeted liposomal imaging agents provide enhanced contrast, prolonged circulation time, and site-specific imaging capability, improving early disease detection ^[30].

• Antimicrobial and Antiviral Therapies

Liposomes have shown promise in encapsulating antibiotics, antiviral agents, and antimicrobial peptides to enhance efficacy, reduce toxicity, and overcome resistance mechanisms.

• Notable Research:

Liposome-encapsulated ciprofloxacin (Lipoquin®) and inhalable formulations for treating lung infections are under active clinical development ^[31].

5. Advantages and Limitations of Liposomes

Liposomes offer significant advantages as drug delivery systems, but their use also comes with certain limitations. Understanding both sides is crucial to optimize their design and application in pharmaceutical and biomedical fields^{. [32]}

• Advantages of Liposomes

• Improved Drug Solubility and Bioavailability

One of the most significant advantages of liposomes is their ability to enhance the solubility of poorly water-soluble drugs. Hydrophobic drugs can be encapsulated within the lipid bilayer, while hydrophilic drugs can be trapped in the aqueous core, thus increasing the bioavailability and therapeutic potential of many compounds.

• Reduced Toxicity and Side Effects

Liposomes help reduce the systemic toxicity of encapsulated drugs, particularly in chemotherapy. For example, liposomal formulations of doxorubicin (Doxil®) and amphotericin B (AmBisome®) have reduced the adverse effects, such as cardiotoxicity and nephrotoxicity, compared to conventional formulations. This enhancement is mainly due to the ability of liposomes to control drug release and target specific tissues, thereby sparing ^[33] healthy organs.

• Controlled and Sustained Drug Release

Liposomes can be engineered to provide controlled and sustained release of drugs. The release rate can be modulated by altering the lipid composition, surface charge, or incorporation of stimuli-responsive materials (e.g., pH-sensitive liposomes). This property is particularly useful in applications where prolonged therapeutic action is needed, such as in cancer therapy and chronic conditions.

• Targeted Delivery

Liposomes can be modified with specific ligands, antibodies, or peptides on their surface, allowing for targeted drug delivery to specific cells or tissues. This enables liposomes to exploit receptor-mediated endocytosis, which is particularly beneficial in cancer therapy, where tumor cells overexpress certain receptors. This targeting reduces the nonspecific uptake of drugs by healthy cells and enhances the therapeutic index^{. [34]}

• Biocompatibility and Biodegradability

The natural phospholipid composition of liposomes makes them biocompatible and biodegradable, minimizing immune responses and inflammatory reactions. This characteristic makes them suitable for a wide range of pharmaceutical and cosmetic applications ^[35].

LIMITATIONS OF LIPOSOMES

• Instability and Storage Issues

Despite their many advantages, liposomes are prone to physical instability, such as aggregation, fusion, and leakage, especially when exposed to environmental factors like temperature and pH variations. This instability can lead to reduced drug encapsulation efficiency and unpredictable drug release profiles. As a result, liposome formulations often require careful storage conditions, such as refrigeration. ^[36]

• High Manufacturing Costs

The production of liposomes is a complex and costly process. The need for high-quality materials (e.g., phospholipids, cholesterol), specialized equipment (e.g., extruders, sonicators), and rigorous quality control measures contributes to the high cost of manufacturing liposomal formulations. These factors can hinder the widespread commercial availability of liposomal drug products, particularly in low-resource settings.

• Limited Drug Load Capacity

While liposomes can accommodate both hydrophilic and lipophilic drugs, their drug loading capacity is often limited, particularly for hydrophobic drugs. Achieving high drug loadings without compromising liposome stability remains a challenge. This limitation may necessitate larger doses, which could increase the cost and potentially lead to undesirable side effects ^[37].

• Biological Barriers

Liposomes may face challenges in crossing biological barriers, such as the blood-brain barrier (BBB), gastrointestinal tract, and skin. Although surface modifications can enhance liposome penetration, achieving efficient delivery across these barriers remains a major hurdle, particularly for certain types of liposomes, such as those used for gene therapy or central nervous system (CNS) targeting.

• Immunogenicity and Complement Activation

While liposomes are generally considered biocompatible, repeated administration of liposomal formulations can trigger immune responses, including complement activation. This could lead to accelerated clearance by the mononuclear phagocyte system (MPS), reducing the therapeutic efficacy of liposome-based drug delivery systems ^[38].

5. Future Perspectives in Liposome Technology

The development of liposomal formulations has progressed significantly over the past few decades, yet there remain numerous opportunities for innovation. Advances in liposome technology are focused on overcoming current limitations, expanding their applications, and improving their clinical efficacy. Some key areas of development include:

• Smart Liposomes and Stimuli-Responsive Systems

Recent research has focused on designing "smart" liposomes that can respond to specific environmental stimuli such as pH, temperature, light, or enzyme activity. These liposomes are engineered to release their drug payloads only under specific conditions, offering highly controlled and targeted therapy. Such systems are particularly promising for cancer therapy, where tumor-specific pH or temperature changes can trigger localized drug release, minimizing damage to healthy tissues. ^[39]

• Liposomes for RNA and Gene Therapy

With the rise of gene and RNA-based therapies, liposomes have gained attention as carriers for mRNA, DNA, and siRNA delivery. Liposomes can encapsulate these nucleic acids and protect them from degradation, facilitating efficient cellular uptake. Recent advancements in lipid nanoparticle (LNP) technology have significantly improved the delivery of mRNA vaccines, such as those for COVID-19, and similar formulations may soon be applied to a range of genetic diseases ^[40].

• Targeted Liposomes for Personalized Medicine

One of the most promising directions for liposome development is their use in personalized medicine. Liposomes can be modified with ligands, antibodies, or peptides to specifically target individual patient characteristics, such as unique genetic markers or specific tumor profiles. Personalized liposomal drug delivery systems could significantly enhance the efficacy and safety of treatments, especially in oncology.

• Scale-Up and Manufacturing Innovations

Despite the clinical success of several liposomal formulations, large-scale manufacturing remains a major challenge. Innovations in manufacturing processes, such as microfluidic techniques and high-throughput methods, aim to improve scalability, reproducibility, and cost-effectiveness. Overcoming these challenges will be key to bringing liposomal drug delivery systems to a broader range of therapeutic areas and patient populations ^[42].

5. Liposomes in Combination Therapies

Liposomes are increasingly being explored in combination therapies, where they serve as versatile carriers capable of delivering multiple therapeutic agents simultaneously. Combination therapies involve using more than one treatment approach to enhance the efficacy of a drug, reduce side effects, and overcome drug resistance. The ability of liposomes to encapsulate and deliver multiple agents, such as chemotherapeutic drugs, biologic therapies, and gene therapies, has made them a promising tool in various therapeutic areas, particularly in oncology and infectious diseases^{. [43]}

• Liposomes in Cancer Combination Therapies

One of the most significant areas where liposomes have made an impact is in oncology, where they are used in combination with traditional chemotherapies, targeted therapies, and immunotherapies. The challenge in cancer treatment lies in the ability to deliver high concentrations of drugs to the tumor site while minimizing toxicity to healthy tissues. Liposomes improve the pharmacokinetics and bioavailability of chemotherapeutic agents, offering a platform for combination treatments that address both the tumor and the microenvironment.

• Liposomal Chemotherapy with Targeted Agents

Liposomes can be used to deliver a combination of chemotherapeutic drugs and targeted therapies. For example, liposomal doxorubicin (Doxil®) is often used in combination with monoclonal antibodies or tyrosine kinase inhibitors to improve the targeting of tumour cells while reducing systemic side effects. The targeted delivery of drugs within liposomes to specific tumor cells enhances the therapeutic effect and decreases the risk of drug resistance that can arise from monotherapy.

• Liposomal Chemotherapy with Immunotherapy

In addition to chemotherapy, liposomes are being explored as delivery systems for immunomodulatory agents such as immune checkpoint inhibitors, cytokines, and vaccines. A liposomal formulation of cytokines like IL-2 or GM-CSF has been used in combination with chemotherapy to boost the body’s immune response against cancer cells. By encapsulating both the chemotherapeutic drug and immune-activating agents, liposomes can improve the synergistic effects of these treatments while reducing the immunosuppressive side effects that may arise from systemic administration of these agents.

• Overcoming Chemoresistance

Chemoresistance is a major challenge in cancer treatment, where tumours develop mechanisms to evade the effects of chemotherapy. Liposomes can help overcome this issue by co-delivering chemotherapy drugs with gene therapy or RNA-based therapeutics, such as siRNA or miRNA molecules, that target specific drug resistance pathways. This dual therapy approach can effectively bypass resistance mechanisms and enhance the anticancer efficacy of the drug treatment ^[44].

• Liposomes in Infectious Disease Combination Therapies

Liposomes have also shown promise in infectious disease treatments, where they can be used in combination with antibiotics, antifungals, or antivirals. In these applications, liposomes act not only as drug carriers but also as agents that can modify the pharmacokinetics and bioavailability of existing therapeutics, enhancing their efficacy.

• Liposomal Antibiotics and Antifungal Agents

In the case of systemic infections, liposomes are being used to deliver antibiotics and antifungal agents more effectively. For example, liposomal amphotericin B is used for the treatment of fungal infections, and liposomal formulations of antibacterial agents such as encapsulated ciprofloxacin have been developed for more efficient targeting of bacterial infections. The use of liposomes enhances the therapeutic index by increasing the concentration of drugs at the site of infection while reducing toxic side effects in healthy tissues.

• Liposomes in HIV and Viral Therapies

Liposomes have also been explored for antiviral therapies, particularly in the treatment of HIV. Liposomal formulations of antiretroviral drugs (ARVs) are being investigated to improve drug stability, bioavailability, and patient compliance. Liposomes can also be used to co-deliver multiple ARVs, ensuring synergistic effects while reducing the required dosage of individual drugs, thus minimizing the side effects and toxicity associated with combination antiretroviral therapy (cART) ^[45].

• Advantages of Liposomes in Combination Therapies

The use of liposomes in combination therapies offers several significant advantages:

• Improved therapeutic outcomes: By delivering multiple agents simultaneously, liposomes can enhance the synergistic effects of drugs, which leads to better disease management and reduced therapy failure.
• Reduced side effects: Liposomes help target drug delivery to the diseased site, sparing healthy tissues from unnecessary exposure and reducing the systemic side effects often associated with chemotherapy and other treatments.
• Overcoming barriers: Liposomes can encapsulate both hydrophilic and lipophilic drugs, allowing for the combination of agents that may otherwise be difficult to co-administer due to their differing solubility profiles.
• Increased drug stability: Liposomes protect sensitive therapeutic agents (e.g., proteins, RNA, and some chemotherapeutics) from degradation, ensuring their stability and extended release at the target site^{. [46]}

• Challenges and Future Directions

Although liposomes have enormous potential for combination therapy, there are several issues that must be resolved. These include concerns about combination products' cost, scalability, and regulatory approval. Furthermore, the therapeutic success of such therapy depends on the stability and compatibility of the many drugs included in the liposome formulation. The development of more advanced, tailored systems that can distribute several therapeutic agents in a regulated and predictable way is essential to the future of liposome-based combination therapies. The accuracy and effectiveness of these treatments could be further improved by research into smart liposomes that react to certain environmental cues or tumor markers. ^[47]

CONCLUSION

Liposomes have revolutionized the field of drug delivery by offering a flexible, biocompatible, and efficient platform for the encapsulation and targeted delivery of therapeutic agents. Their ability to carry both hydrophilic and lipophilic drugs, improve pharmacokinetics, reduce systemic toxicity, and enhance site-specific action has made them indispensable in modern pharmaceutical research. From cancer and infectious diseases to gene therapy and vaccine delivery, liposomes have demonstrated significant clinical potential. Advances in liposomal engineering, including PEGylation, ligand-targeting, and stimuli-responsive systems, continue to expand their applications. Furthermore, the integration of liposomes in combination therapies underscores their role in overcoming multidrug resistance and enhancing treatment efficacy. Despite challenges in large-scale production, regulatory approval, and stability, ongoing research and technological advancements promise to further refine liposomal systems for broader clinical translation. As nanomedicine continues to evolve, liposomes will remain at the forefront, contributing significantly to the development of safer and more effective therapeutic strategies.

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