1 Holy Grace Academy of Pharmacy, Mala, Thrissur
2,3,4,5,6,7 Nirmala College of Health Science, Chalakkudy, Thrissur
Cubosomes are self-assembled nanostructured liquid crystalline particles derived from lipid-based bicontinuous cubic phases and stabilized by polymeric surfactants. Their architecture, consisting of a continuous lipid bilayer with interwoven aqueous channels, provides a large internal surface area that enables the efficient encapsulation of hydrophilic, hydrophobic, and amphiphilic molecules. Compared to conventional liposomes, cubosomes offer higher drug-loading capacity, enhanced stability, biocompatibility, and controlled release properties. They can be fabricated by top-down or bottom-up approaches using amphiphilic lipids such as monoolein and phytantriol, while surface functionalization of the polymeric corona facilitates targeted and site-specific delivery. These features allow cubosomes to sustain drug release, protect labile molecules, and improve bioavailability, supporting their application across diverse administration routes including ocular, oral, intravenous, transdermal, and topical delivery. Recent studies highlight their promise in the delivery of anticancer agents, peptides, proteins, nucleic acids, and cosmeceuticals. Despite these advantages, challenges remain in large-scale manufacturing, viscosity-related processing, and long-term stability. However, ongoing advances in formulation optimization, functionalization, and characterization continue to enhance their translational potential. This review summarizes the composition, preparation techniques, drug-loading strategies, and therapeutic applications of cubosomes, while addressing their limitations and future prospects as multifunctional nanocarriers in next-generation drug delivery and biomedical systems.
Lipid-based nanocarriers have emerged as a versatile class of drug-delivery systems due to their inherent biocompatibility, biodegradability, and ability to encapsulate a wide range of therapeutic agents. Among these, non-lamellar mesophasic nanostructured materials derived from lyotropic liquid crystals (LLCs) have gained increasing attention for biomedical applications. In particular, cubosomes, which are self-assembled bicontinuous cubic-phase nanostructures, represent a unique and highly promising platform. These nanoparticles are formed when amphiphilic lipids such as monoolein or phytantriol spontaneously organize into a three-dimensional cubic lattice in excess water, stabilized by a polymer-based outer corona. Their architecture is characterized by a continuous lipid bilayer separating two interpenetrating aqueous channels, resulting in a large internal surface area and high structural complexity.
This intricate geometry confers several advantages over conventional lamellar systems such as liposomes. The bicontinuous cubic phase provides significantly greater membrane surface area for the incorporation of membrane proteins, small molecules, and bioactive compounds, while the interconnected aqueous channels enable efficient entrapment of hydrophilic, hydrophobic, and amphiphilic agents. Furthermore, the polymer corona not only stabilizes the cubosomes under physiological conditions but can also be functionalized to impart targeting capabilities, thereby enhancing site-specific delivery and reducing off-target effects.
Recent years have witnessed rapid progress in the design, engineering, and biomedical application of cubosomes. Their ability to encapsulate and sustain the release of both small-molecule drugs and large biomolecules such as peptides, proteins, and nucleic acids has positioned them as attractive candidates for next-generation nanomedicine. Controlled drug release can be achieved through surface modification, ligand attachment, or tuning of the lipid composition to alter pore size and fluidity. Importantly, their self-assembling nature enables relatively simple and scalable production through top-down or bottom-up fabrication approaches, making them compatible with translational research and industrial-scale applications.
Beyond drug delivery, cubosomes have demonstrated potential in membrane bioreactors, artificial cells, and biosensors, owing to their resemblance to biological membranes and their ability to host functional proteins. Their highly ordered nanostructure can also be harnessed in imaging, diagnostics, and vaccine delivery. However, despite these advances, challenges remain in optimizing large-scale manufacturing, ensuring reproducibility, and addressing issues such as in vivo stability, biodistribution, and immune responses.
In this review, we present a comprehensive overview of the current state of cubosome research. We outline their composition, structural features, preparation methods, encapsulation strategies, and mechanisms of drug loading and release. Furthermore, we highlight recent advances in their biomedical applications, discuss ongoing challenges, and provide guidelines for the rational design of cubosome-based systems aimed at clinical translation.
Figure 1 : Review of the state of the Drug Delivery
Reproduced from Abourehab et al. (2022), J. Mater. Chem. B : Cubosomes as an emerging platform for drug delivery: a review of the state of the art” journals of materials chemistry B issue 5 .
IDEAL PROPERTIES OF CUBOSOMES
TYPES OF CUBOSOMES
Cubosomes can be classified based on several criteria, primarily internal structure (symmetry) and channel connectivity. Here’s a breakdown of the main types of cubosomes:
These types correspond to the specific cubic phase group that define the internal architecture of the cubosomes.
These defines how the internal aqueous channels interact with external environment.
ADVANTAGES OF CUBOSOMES
DISADVANTAGES OF CUBOSOMES
APPLICATIONS
In Recent days, some anticancer drugs have been naturally packaged (encapsulated) in bulk& are characterized by physiochemical properties. The special structure of these promising Nano carriers indicates its application in this therapy.
Various techniques have been investigated to specifically Target Nano-drugs to tumour regions of the body with active and passive targeting of cancer cells in preclinical & clinical studies to target nano-medicines to tumour regions in the body by active and passive targeting of cancer Deals with viral infections.
Oral Drug delivery system presents many challenges such as Large Molecules, Water solubility, less absorption. Cubosomes type of preparation can overcome all these challenges. They also have another advantage, which is to release the drug at different sites and this is necessary in cases where the drug has a narrow absorption E.g.; Dexamethasone: Cubosomes improve the pre ocular retention time and ocular bioavailability of dexamethasone which is used in the treatment of anterior ocular inflammation
Compared to liposomes cubosomes have promising properties of high drug loading. It is also the most suitable carrier for injection. Some of the insoluble small molecules are supplied by cubosomes .it also act as a precursor for the delivery of viscous substances. Therefore, upon subcutaneous injection the lamellar phase is initially fluid but later absorbs water for the environment and Transforms into the cubic phase. It is involved in forming a depot in situ
Cubosomes are basically bio-Adhesive in Nature and High Permeability which help in increase liquid fluidity and enhance the skin permeability of the drug. So we are used them in mucosal as well as topical drug delivery systems.
Eg: Capsaicin -. Cubosomes provided sustained release of capsaicin, prolonged skin retention with no irritation to skin and render capsaicin stable under strong light and high temperature. Capsaicin Used in the treatment of psoriasis, pruritus, and contact allergy
Cubic Phase is inherently more bio adhesive and convenient for topical & mucosal deposition and delivery of various drugs
Used to increase the therapeutic effect of drug example: Insulin patches and Scopolamine patches used to cure motion sickness [6
Dosage form challenges, low solubility low absorption, large molecular size. Cubosomes technology provides drug release at different absorption sites having narrow absorption window. This type of dosage form is important for dugs clopidogrel bisulphate myocardial infarction & stroke and increase release of drug.
Latest evolution by L” oreal and Nivea in the field of cubosomes is they had prepared emulsion (oil in water type) for cosmetic purposes.
Deals with viral infection lipids used in cubosomes, formulations such as monoglycerides, have bactericidal activity. they are therefore suitable for the treatment of STD Caused by both virus (HIV) and bacteria (Genorrticae).
Figure 2 : Cubosome; design, development & Targeted drug delivery application
Reproduced from Hassaan Umar, Habibah AWahab , Amirah Mohd Gazzali, Hafsa Tahir, Waqas Ahamad :Cubosomes ; Design ,development and tumour-targeted drug delivery applications in MDPI polymers (PubMed) , 2022 July 31 ;14(15) :3118
TRANSDERMAL DRUG DELIVERY OF CUBOSOMES
The stratum corneum, being the highly organized outermost skin layer, acts as a major barrier to transdermal drug delivery. Cubosomes, owing to their bioadhesive and structural properties, have emerged as promising carriers for topical and mucosal drug delivery. Their bioadhesion, largely attributed to glyceryl monooleate (GMO), enhances drug retention within skin layers, thereby improving therapeutic efficacy.
Recent studies highlight several dermatological applications of cubosomes, including:
FORMULATION TECHNIQUES OF CUBOSOMES
Cubosomes are generally prepared using two principal approaches: the top-down and bottom-up methods. In both cases, the use of a stabilizer such as poloxamer 407 (F127) is essential to prevent aggregation of the dispersed particles. The selection of the preparation strategy mainly depends on the desired stability, biocompatibility, and controlled drug release profile of the final formulation.
Top-Down Approach
The top-down method is the most widely employed strategy for cubosome production. It typically involves two stages:
Figure 3 : Schematic representation of cubosome preparation using the top-down method.
Reproduced from Rutuja Suresh Jagtap ,Prajkta Sadanand Ingale, Khushbu Santosh Kahar, Dipali Dodtale B. D. Tiwari : A Review Article On Cubosomes AS A Novel "Drug Delivery Systems.International Journal Of Pharmaceutical Sciences.2010.Volume 02 ; Issue 06
A cubic phase–forming lipid (e.g., glyceryl monooleate) is mixed with a stabilizer to yield highly viscous cubic aggregates.
The bulk phase is dispersed in aqueous medium using high-energy input methods such as high-pressure homogenization or probe sonication, resulting in nanosized cubosomal particles. Cubosomes prepared by this method have demonstrated good stability against aggregation for extended periods (up to one year). However, the requirement of intense energy input during dispersion limits its application in large-scale production. Moreover, this technique is not ideal for formulations containing thermolabile or sensitive bioactive molecules, such as peptides and proteins, since high shear and temperature may cause degradation.
Bottom-Up Approach
Fig 4 : Schematic representation of cubosome preparation using the bottom-up method
Reproduced from Saffron J. , Bryant , Edler : Bottom-up cubosome synthesis without organic solvents.Journal of Colloid and Interface Science.2021;volume 601;Pages 98-105.
The bottom-up strategy, also known as the solvent dilution method, relies on the spontaneous self-assembly of lipid nanostructures at low energy input. In this approach, a mixture of lipid, stabilizer, and a hydrotrope is diluted with an excess of water, leading to the controlled formation of cubosomes.
Hydrotropes play a critical role in this technique. They improve the aqueous solubility of hydrophobic lipids by forming transient complexes and, at the same time, prevent premature formation of bulk liquid crystals. Commonly used hydrotropes include urea, sodium alginate, and sodium benzoate. By modulating solubilization, they enable the preparation of cubosomes at relatively mild conditions.
Compared with the top-down method, the bottom-up approach requires considerably less energy, making it more suitable for encapsulating temperature-sensitive drugs such as peptides, proteins, or vaccines. Furthermore, the homogeneous distribution of stabilizers on the nanoparticle surface enhances the long-term stability of the resulting formulation.
MECHANISM OF PENETRATION IN CUBOSOME
The drug release mechanism from cubosomes is based on the principle of drug diffusion, where the concentration gradient of the drug across the cubosomes is the driving force of the diffusion. Therefore, the drug release rate from cubosomes is generally coincidental with the Higuchi or Fick diffusion equation. There are many factors influencing the drug release rate, such as drug solubility, diffusion coefficient, partition coefficient, cubic liquid-crystalline geometry, pore size and distribution, interface curvature, temperature, pH, and ionic strength of the release medium. The release mechanism of several hydrophilic model drugs from the cubic and reversed hexagonal liquid crystalline was investigated. These studies indicated that diffusion is the predominant mechanism of drug release, and the drug release rate from cubic ones is faster than the hexagonal liquid crystalline. Furthermore, the in vivo drug release profiles of 14C-glucose from cubosomes and hexagonal phase were consistent with the in vitro release profiles, which indicated the nanostructure of cubosomes and the nature of lipid could be utilised to control the release rate of hydrophilic drugs. But it is difficult for the hydrophobic drug to escape from the cubosomes in vitro due to the affinity of the drug with the hydrophobic domain in the cubic phase. Hence, the release profiles of hydrophobic drug-loading cubosomes in distilled water media (pH 6.5) and digestion media (0.1 M Hydrochloric acid) were investigated and found that the drug release rate in the digestion media was drastically improved. Also, it is reported that the plasma concentration of Silymarin in vivo showed an increased drug release rate from cubosome formulation as compared to Legalon®, a commercial capsule formulation.
EVALUATION TECHNIQUES OF CUBOSOMES
EE% of cubosomes= [(Ct-Cf)/Ct] ×100
Cf = not encapsulated in cubosomes
Ct = Total drug concentration
REGULATORY COMPLIANCE
Ensure that cubosome meet regulatory requirement for cosmetic ingredients, including safety assessments & labelling regulation.
Maintain through documentation of all testing procedures and results to comply with regulatory standard and for potential product approval.
TOXICITY OF CUBOSOME
Toxicity studies are scientific investigations that assess the harmful effects of chemical substances, drugs, or other agents on living organisms. These studies are crucial for understanding the potential adverse effects of a substance and for ensuring its safety before it can be used by humans or released into the environment.
A cytotoxicity test is a biological assay used to assess the toxic effects of a substance on cells, determining its potential to damage or kill them. These tests are crucial for evaluating the safety of materials, especially in medical devices, pharmaceuticals, and other products that come into contact with living tissue. Cytotoxicity tests help determine if a substance can cause cell death, inhibit growth, or induce other adverse effects.
CONCLUSION
Cubosomes represent a unique class of lipid-based nanocarriers characterized by their internal liquid crystalline nanostructure. They are typically prepared from amphiphilic lipids that self-assemble in aqueous environments in the presence of suitable stabilizers. Owing to their distinctive architecture and biocompatibility, cubosomes have emerged as versatile platforms for drug delivery.
Recent studies have highlighted their potential in diverse routes of administration. In ocular delivery, cubosomes have demonstrated enhanced residence time, improved bioavailability, and minimal irritation. Oral administration has shown their ability to increase the absorption of poorly water-soluble drugs, protect labile compounds from enzymatic degradation, and facilitate targeted delivery. Furthermore, cubosomes provide an effective vehicle for transdermal applications, with improved skin permeation and low irritation potential. Their utility has also been reported in the delivery of chemotherapeutic agents, where they offer enhanced targeting and reduced systemic side effects.
Overall, cubosomes are gaining significant attention in preclinical investigations as promising carriers for a wide range of therapeutic agents. Their structural adaptability, capacity for high drug loading, and potential for targeted delivery make them strong candidates for translation into clinical drug delivery system.
REFERENCES
Raslamol K, Remya Bernard, Abhirami, Aleena Shabu, Asika Sathian, Aswathi T B, Chinmaya A B, The Cubic Revolution: Cubosomes in Pharma and Cosmetics, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 12, 3690-3703. https://doi.org/10.5281/zenodo.18062436
10.5281/zenodo.18062436
