In this article, Creative Biolabs provides an overview of the various graphene oxide (GO)-based delivery strategies employed in today's biomedical field.

Introduction to Graphene Oxides (GOs)^2–5

Definition of Graphene Oxides

Graphene is a monolayer of aromatic carbon atoms covalently bound and organized in a hexagonal lattice structure (Figure 1). It has excellent mechanical strength, remarkable compatibility, a large surface area, and high electrical and thermal conductivities. Compared with graphene, graphene oxide (GO) is an oxidized graphene derivative. It contains oxygen-containing functional groups (hydroxyl, carboxyl, epoxy) across its lattice (Figure 1). These functional groups confer GO with unique properties such as water dispersibility, chemical tunability, and strong adsorption capacity for polar polymers or molecules. Due to these properties, graphene oxides are widely utilized in biomedical fields, including targeted drug delivery, bioimaging, biosensors, and tissue engineering. Beyond biomedical fields, GO also finds applications in electronics, such as flexible screens and solar cells, in energy storage, including batteries and supercapacitors, and in environmental applications, including water treatment.

Fig. 1: The graphene (G) and graphene oxide (GO) structures¹.

Market Size and Industry Growth Trends

The global graphene oxide market is currently experiencing significant growth. The global graphene oxide market is valued at $243.1 million in 2024, and is projected to reach $327.3 million in 2025 and $2.75 billion by 2032, with a compound annual growth rate (CAGR) of 35.5%. The fast-growing market is likely driven by advancements in nanotechnology and the expanding applications of GO in biomedical fields and various industries, including electronics and energy sectors.

Graphene Oxide Properties

As the introduction mentioned, GO is a two-dimensional carbon lattice with defects and functional oxygen groups. Carboxylic groups are usually present on the edges of GO, whereas epoxide and hydroxyl groups are located on the basal plane of GO (Figure 1). These structural features bestow GOs with various biochemical properties, making GOs particularly attractive for multiple biomedical and industrial applications.

Key properties of GOs:

Graphene Oxide Synthesis

Graphene oxide can be synthesized using four basic methods: the Staudenmaier, Hofmann, Brodie, and Hummers methods. The most common method of GO production is the Hummers method, which oxidizes graphite using concentrated acids and strong oxidants. Although this method is safe and efficient, it generates toxic gases, including nitrogen dioxide, dinitrogen tetroxide, and chlorine dioxide. Recent method development focuses on eco-friendly synthesis. For instance, a modified Hummer's method is being developed to reduce environmental impact, increase scalability, and enhance biomedical safety. The modified Hummers method is described below (Figure 2):

1. Initial Mixture Preparation
   Graphite is mixed with concentrated H₂SO₄ and NaNO₃ in a ratio of about 1:25:0.5. In this step, the acid intercalates and protonates the graphite layers. At the same time, nitrate ions expand and partially oxidize them, creating space for later oxidation.
2. Controlled KMnO₄ Addition
   KMnO₄ is carefully added to the treated graphite (about 2–5 parts per 1 part graphite) while keeping the mixture near 20 °C in an ice bath. In this step, KMnO₄ acts as the primary oxidizing agent, introducing oxygen functionalities into the graphite layers. At the same time, the low temperature prevents excessive heat and preserves the carbon lattice for controlled oxidation.
3. Quench & Heat
   Distilled water is carefully added at a ratio of approximately 50 parts to 1 part graphite, while maintaining a temperature below 20 °C. Then, 150 more parts are added, and the temperature is heated to 95 °C. In this step, the first water addition safely quenches the excess oxidant, and the subsequent dilution with heating drives the oxidation to completion, exfoliating the graphite into a dark brown graphene oxide slurry.
4. Final Oxidation & Purification
   Approximately 10 parts of 30% H₂O₂ are added to 1 part graphite, and the mixture is stirred until the suspension turns bright yellow. Then the suspension is repeated washed with 5% HCl and distilled water until the solution is neutral. In this step, hydrogen peroxide removes manganese residuals, and the acid washes remove metal salts, leaving purified graphene oxide.
5. Drying
   The product is dried at 60 °C for 24 h to obtain a stable and storable GO powder.

Fig. 2 Step-by-step of graphene oxide (GO) synthesis by modified Hummers⁴.

GO Functionalization for Drug Delivery

To optimize GO as a drug delivery nanocarrier, functionalization of GOs is applied to increase solubility, biocompatibility, drug-loading, and release efficiency, and cell-targeting ability (Figure 3). GO functionalization can be generally divided into covalent, noncovalent, and hybrid (combined) approaches, each with distinct mechanisms and applications.

Covalent Functionalization: Stable and Permanent Modification

Covalent bonding refers to the covalent attaching of molecules (i.e., polymers, peptides, or drugs) to the oxygen-containing groups (e.g., carboxyl or hydroxyl) on the GO surface through chemical reactions. It forms strong and stable modifications, making it suitable for applications requiring durability (e.g., long-term drug delivery).

Key Mechanisms & Examples:

• Amide Bond Formation: Crosslinkers bind amine-containing molecules (e.g., PEG-NH₂, chitosan) to GO carboxyl groups. In the cytotoxicity assay performed on fibroblast cells, PEGylated GO (NGO-PEG) is seen to decrease in vitro cytotoxicity by 40–60% relative to raw GO.
• Silane Modification: Silane agents (e.g., APTES) react with GO's hydroxyl groups to introduce amino or epoxy groups, enabling further conjugation with drugs or targeting ligands.
• Polymer Grafting: Covalently attaching biocompatible polymers (e.g., polyacrylic acid/PAA, and polyacrylamide/PAM) to the surface of GO enhances its mechanical strength and drug-loading efficiency. For instance, NGO-PAA shows 2x higher loading capacity of hydrophilic drugs than unmodified GO.

Advantages:

• Stable conjugation (resists dissociation in biological fluids).
• Precise control over surface chemistry (e.g., targeting ligand density).

Noncovalent Functionalization: Gentle and Flexible Modification

Noncovalent functionalization employs weak intermolecular interactions (π-π stacking, hydrophobic interactions, hydrogen bonding) to attach molecules to the basal plane of GO. This strategy maintains the pristine properties of GO (e.g., electrical conductivity) and is well-suited for sensitive cargos (e.g., natural therapeutics, proteins).

Key Mechanisms & Examples:

• π-π Stacking: GO's hexagonal carbon lattice can bind to aromatic molecules (e.g., curcumin, doxorubicin, plant-derived phenolics). In the tumor treatment, curcumin-loaded GO via π-π stacking can achieve a drug content of 4.5–29 wt% and exhibit pH-responsive release.
• Hydrophobic Interactions: Hydrophobic segments of molecules (e.g., lipids, essential oils) can be attached to GO's nonpolar basal plane, thereby improving the solubility of water-insoluble drugs. For example, compared with the 35% release efficiency of free drugs (a hydrophobic flavonoid), the release efficiency was increased to 91% when the hydrophobic flavonoid was loaded onto PVP-functionalized GO via hydrophobic forces.
• Hydrogen Bonding: GO's hydroxyl or epoxy groups can form hydrogen bonds with molecules such as dextran or peptides, thereby enhancing biocompatibility.

Advantages:

• No harsh chemicals (preserves natural therapeutic potency).
• Easy to scale (no complex synthesis steps).

Hybrid Functionalization: Synergizing Covalent & Noncovalent Bonds

Hybrid approaches combine both strategies to maximize GO's performance.

Examples:

• Dual-Drug Delivery: PEGylated GO (covalent amide bonds with PEG-NH2) loads cisplatin (covalent) and doxorubicin (noncovalent π-π stacking). This system achieves 36.7–37.6% drug loading and 64.6–65.7% controlled release, with synergistic anticancer effects in MCF-7 cells.
• Targeted Antimicrobial Systems: Aptamer-conjugated GO (covalent bonding) loads berberine (noncovalent π-π stacking) to target MRSA. The hybrid system reduces bacterial viability by 99.9% and prevents the formation of biofilms.

Fig. 3 The functionalization of GO⁶.

Graphene Oxides in Biomedicine

Graphene oxides (GOs) are endowed with multiple properties that have led to the development of a wide range of biomedical applications. The following represent some of the major areas where GOs have found their application.

Drug and gene delivery

Graphene Oxide (GO) has a large surface area, colloidal stability, and tunable loading/ release property; thus, it can serve as a potential nanocarrier for drug delivery. Therapeutic drugs can be loaded onto GOs via π-π stacking or hydrophobic interactions with pH- or photo-responsive release. In gene delivery, functionalized GOs have been used to deliver siRNA/plasmid DNA to target tumor cells, thus inhibiting their growth.

Phototherapy

Ligand-mediated targeting utilizes specific interactions between receptors and ligands to direct LNPs to the target cells/tissues. Two primary methods are applied for attaching ligands to LNPs: post-insertion and direct conjugation.

Bioimaging

GOs are fluorescent-emitting upon excitation at specific wavelengths (350–650 nm) for optical imaging. GOs can also serve as carriers of contrast agents (e.g., gadolinium-decorated graphene oxides) for magnetic resonance imaging (MRI) or photoacoustic imaging.

Biosensing

GOs can be used for detection either through fluorescence quenching or by their electrical properties. Interactions with single-stranded DNA (ssDNA) allow for sequence-specific recognition. The surface of GO can be functionalized with various biomolecules that have high affinity for a specific biomarker, enabling detection and, thus, diagnostic use.

Tissue engineering

GOs/rGOs can help with tissue regeneration via supporting stem cell proliferation and differentiation. The incorporation of GOs/rGOs in scaffolds can improve their electroconductivity, which is essential for cardiac and nerve regeneration. GO-incorporated poly (lactic-co-glycolic acid) (PLGA) scaffolds, for example, have been shown to support better mesenchymal stem cell growth.

Antibacterial applications

GOs could damage the bacterial membrane, which subsequently results in oxidative stress, thus suppressing the growth of pathogens (such as E. coli and S. aureus).

GO-Based Drug Delivery Strategies

Passive Targeting

Because tumor blood vessels are leaky (with pores of 400–800 nm), GO nanoparticles can exploit the enhanced permeability and retention (EPR) effect, thereby allowing for GO accumulation in tumor tissues. In this way, the therapeutic efficacy of encapsulated drugs is improved significantly.

Active Targeting

By conjugating GO with specific ligands, such as antibodies or peptides, it becomes possible to direct the nanoparticles to particular cell types or tissues, improving specificity and minimizing off-target effects.

Controlled Drug Release Systems

GO can be engineered to release its payload in response to specific stimuli, such as changes in pH, temperature, or the presence of certain enzymes. This allows for controlled and sustained release of the drug.

Co-delivery of Multiple Therapeutics

GO's large surface area allows for the simultaneous loading of multiple therapeutic agents, allowing for combination therapies, such as therapies that target different pathways.

Other Applications of Graphene Oxides

GO's versatility enables applications across the industrial field.

Catalysis

GO has been used as a catalyst or catalyst support in a wide range of organic reactions and cross-couplings. The presence of oxygen groups can provide active sites for the binding and activation of reactants. In composites, GO is used to improve the catalytic activity of other materials; for example, the use of a GO–metformin–Cu composite achieved yields of 99% in a model reaction.

Photocatalysis

GO can be used for the degradation of pollutants, hydrogen production from water splitting, and carbon dioxide reduction. Its band gap is also tunable to absorb a broad range of light for photocatalytic applications.

Electrochemistry

GO has been used in electrochemical applications such as hydrogen evolution and biosensing. The material's conductivity and high surface area can promote efficient electron transfer in electrochemical reactions.

Environmental Remediation

GO can be used in environmental remediation due to its high surface area and pore structure, which can adsorb heavy metals and degrade volatile organic compounds (VOCs).

Optoelectronics

In the optoelectronics field, GO has been used to improve the electrodes of solar cells. The material can also be used for the sensitive detection of pollutants through fluorescence quenching and Raman enhancement.

Future Directions in Graphene Oxide Research

Efficacy and Safety Evaluation

Although many studies on GO nanocarriers show promising therapeutic effects, a systematic evaluation of their long-term toxicity, biodistribution, and elimination pathways is required. Only with sufficient preclinical and clinical evidence can GO-based nanocarriers move toward regulatory approval and patient use.

Sustainable Production

The production of GO using traditional methods consumes large amounts of strong oxidants and acids, resulting in hazardous waste. In the future, green chemistry will be prioritized, and a scalable and eco-friendly production of GO will be developed by adopting milder oxidants, recyclable solvents, and low-energy processes.

Hybrid Nanomaterials

Multifunctional nanoplatforms that are capable of performing simultaneous drug delivery, imaging, sensing, and even catalysis can be created by combining GO with metals, polymers, or biomolecules. These hybrids will enable simultaneous drug delivery and magnetic or optical tracking of the nanoparticles within the body.

Flexible Electronics

GO can be integrated with wearable biosensors and other flexible electronics. These integrated devices can allow for continuous monitoring of health indicators, such as glucose levels and cardiovascular signals.

Personalized Medicine

Based on patient-specific information, it would be possible to tailor GO-based nanocarriers to optimize drug delivery parameters, including dose, timing, and targeting, thereby achieving proximal efficacy with reduced side effects.

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References

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