The properties of hydrogels, such as biocompatibility, biodegradability, and flexibility, make them outstanding prospects for a range of tissue engineering, medication delivery, and biosensing.⁶ Recent advancements have focused on creating hydrogels that react to outside stimuli (such as temperature or pH) to release medications in a regulated way. These smart hydrogels can improve the release profiles of drugs, ensuring therapeutic levels are maintained over extended periods while reducing side effects.⁷

For the treatment of chronic inflammatory diseases like psoriasis, inflammatory bowel disease, and rheumatoid arthritis, anti-inflammatory medications such corticosteroids and NSAIDs are essential. However, systemic administration often leads to adverse effects, including gastrointestinal issues and organ toxicity. Nanosponges and hydrogels provide targeted delivery, reduce systemic side effects, and enhance therapeutic efficacy by maintaining sustained drug release.^8-10

This review explores the design and properties of nanosponges and hydrogels, emphasizing their role as innovative drug delivery systems. It highlights advancements in their application for anti-inflammatory therapy, addressing challenges like systemic side effects and poor bioavailability. Additionally, it examines development challenges and future prospects, showcasing their potential to revolutionize anti-inflammatory treatment.¹¹

Nanosponges: Fundamentals and Design:

Nanosponges are highly porous, nanoscale materials with a sponge-like structure. They are usually made of biodegradable polymers like polyester, cyclodextrins, and hyper-crosslinked polystyrene (Table 1). The high surface area, tunable pore size, and stable framework allow nanosponges to contain a range of medicinal substances. Their ability to protect drugs from degradation, improve solubility, and control release makes them ideal for drug delivery applications.¹²

Mechanisms of Drug Encapsulation and Release:

1. Encapsulation Mechanisms: Drugs are loaded into nanosponges through physical adsorption, ionic interactions, or covalent bonding, depending on the drug's properties and the surface of the nanosponge's functional groups. Hydrophobic drugs are encapsulated within the porous core, while hydrophilic drugs interact with surface groups.¹⁵

2. Controlled Release: Nanosponges enable sustained release by diffusing the drug through their pores or degrading the polymer matrix under specific physiological conditions. Stimuli-responsive nanosponges further allow release in reaction to enzymes, pH, or temperature, enhancing site-specific delivery.¹⁶

Hydrogels: Basics and Synergistic Integration with Nanosponges:

Characteristics of Hydrogels Relevant to Drug Delivery:

Three-dimensional, hydrophilic networks of polymers called hydrogels may hold a lot of water or biological fluids. Their special qualities make them perfect for applications involving the delivery of drugs.

· Biocompatibility: Hydrogels are non-toxic, minimally inflammatory, and compatible with biological tissues, making them suitable for biomedical applications.¹⁷

· Controlled Release: Their porous structure permits the regulated release of medications via diffusion or polymer degradation.¹⁸

· Stimuli-Responsivenes: Hydrogels can respond to environmental triggers such as pH, temperature, or ionic strength, enabling site-specific drug delivery.¹⁹

Methods of Incorporating Nanosponges into Hydrogels:

Nanosponges are porous, nanoscale carriers primarily made of polymers or cyclodextrin derivatives. Their formulation involves specific techniques tailored to their structural and functional requirements. Below are the common methods used for nanosponge formulation.

Ultrasound-Assisted Synthesis:

This method uses ultrasonic waves to enhance the formation of nanosponges.²⁰ Cyclodextrin is reacted with crosslinking agents (e.g., diisocyanates or pyromellitic anhydride) in the presence of ultrasound energy. The high energy promotes efficient crosslinking and reduces reaction time.²¹

Crosslinking with Crosslinker Agents:

This method involves chemical crosslinking of cyclodextrins or other polymers using agents such as Diphenyl carbonate, Pyromellitic dianhydride, Carbonyldiimidazole.²² Cyclodextrins or polymers are reacted with crosslinkers under controlled conditions. The degree of crosslinking affects the porosity and drug-loading capacity of the nanosponges.

Solvent method:

This technique entails adding a polymer solution to an excess of the crosslinker while keeping the temperature at 10°C for 48hours. Additionally, after cooling the mixture, extra water is added, which causes nanosponges to develop. The produced nanosponges were gathered after being vacuum-filtered. The mixture is purified using a lengthy Soxhlet extraction procedure with ethanol.²³

Advantages of Nanosponge-Hydrogel Composites:

The integration of nanosponges into hydrogels offers synergistic benefits, combining the advantages of both materials.^24-27

Figure 1: Synergistic Benefits of Nanosponge-Integrated Hydrogels

Characterization of Nanosponges Loaded Hydrogels:

Physical and Chemical Characterization:

§ Morphology:

The morphology of nanosponges and hydrogel systems is commonly analyzed employing methods such as transmission electron microscopy and scanning electron microscopy (SEM) (TEM).²⁸ These methods provide insights into the surface texture, porosity, and particle distribution within the hydrogel matrix. For instance, SEM²⁹ images can reveal the porous structure of hydrogels loaded with nanosponges, critical for determining their swelling and drug release properties.^30,31

§ Particle size :

Particle size, typically measured using dynamic light scattering (DLS), influences the stability, drug encapsulation efficiency, and release profile of nanosponges and hydrogels, impacting their bioavailability, penetration, and overall therapeutic effectiveness.^32,33

§ Zeta potential:

Zeta potential measures the surface charge of nanoparticles, indicating colloidal stability. Higher absolute values prevent aggregation by electrostatic repulsion, while lower values suggest instability, affecting drug delivery, bioavailability, and hydrogel-nanosponge interactions.^34,35

§ Swelling Behavior:

Swelling behavior, a key property influencing drug release, is evaluated using gravimetric methods. Hydrogels are immersed in various pH solutions to measure water uptake, providing information about the responsiveness of the hydrogel to environmental stimuli. Swelling studies help assess the compatibility of nanosponges with the hydrogel network.^36,37

Drug Loading Capacity and Release Profile Analysis:

High-performance liquid chromatography (HPLC) and UV-Vis spectroscopy are two spectroscopic or chromatographic techniques used to measure the drug loading capacity of nanosponges in hydrogels.³⁸ These techniques measure the concentration of drugs encapsulated within the system.

For drug release profiling, in vitro studies are performed in simulated physiological conditions, and the amount of drug released is monitored over time using UV-Vis or HPLC. Models like Higuchi or Korsmeyer-Peppas are applied to determine the release kinetics.³⁹

Stability and Compatibility Studies:

§ Stability:

Stability studies involve assessing the structural integrity and performance of the hydrogel-nanosponge system under various conditions, such as temperature, humidity, and light. (DSC)⁴⁰Differential scanning calorimetry and (TGA)⁴¹ thermogravimetric analysis is frequently used to evaluate the materials ability to withstand heat.

§ Compatibility:

Compatibility between the drug, nanosponge, and hydrogel matrix is analyzed using (FTIR)⁴² Fourier-transform infrared spectroscopy and (XRD) X-ray diffraction.FTIR helps identify potential chemical interactions (e.g., hydrogen bonding), while XRD indicates the crystalline or amorphous characteristics of the medication in the hydrogel matrix.⁴³

Evaluation of Therapeutic Efficacy of Nanosponges Loaded Hydrogels:

In Vitro Studies: Drug Release, Biocompatibility, and Cytotoxicity:

§ Drug Release:

Drug release studies in vitro are crucial for evaluating the release profile of nanosponges embedded in hydrogels. These studies are typically performed in mimicked gastrointestinal conditions by simulating physiological conditions with phosphate-buffered saline (PBS) at varying pH levels. Release kinetics are analyzed using models like Higuchi or Korsmeyer-Peppas to assess the rate and mechanism of drug release.⁴⁴

§ Biocompatibility:

Biocompatibility is assessed through cell viability assays (e.g., MTT, CCK-8) using various cell lines (e.g., fibroblasts, keratinocytes). The results determine if the nanosponges and hydrogels induce any adverse reactions in normal cells, ensuring that the system is suitable for clinical applications.⁴⁵

§ Cytotoxicity:

Cytotoxicity studies are critical for evaluating the safety of nanosponges loaded hydrogels. The cytotoxic effects are evaluated using standard protocols like MTT or LDH assays to determine the potential harmful effects of the delivery system on normal cells.⁴⁶

In Vivo Studies: Anti-inflammatory Effects and Pharmacokinetics:

§ Anti-inflammatory Effects:

In vivo anti-inflammatory efficacy is typically evaluated using animal models, such as carrageenan-induced paw edema or lipopolysaccharide (LPS)-induced inflammation. The anti-inflammatory effects of drug-loaded hydrogels are compared with traditional delivery methods, like free drugs or traditional formulations.^47-49

§ Pharmacokinetics:

Pharmacokinetic studies are essential for understanding the drug metabolism, excretion, distribution, and absorption (ADME) delivered via nanosponges in hydrogels. These studies are often conducted in rats or other animal models, using blood sampling to measure drug concentration over time and analyzing parameters such as half-life, bioavailability, and Cmax.⁵⁰

Applications in Anti-Inflammatory Drug Delivery:

Potential Clinical and Therapeutic Applications:

Anti-inflammatory drug delivery systems, particularly those using nanosponges loaded into hydrogels, have shown enormous potential for the management of several inflammatory diseases, such as:

§ Arthritis: Nanosponges embedded in hydrogels can provide sustained and localised release of anti-inflammatory medications, including non-steroidal anti-inflammatory medicines (NSAIDs) and corticosteroids, directly to inflamed joints, minimizing systemic side effects.

§ Wound Healing: These systems can be employed in the management of chronic wounds or skin conditions like eczema and psoriasis, providing localized anti-inflammatory action to promote healing while reducing the inflammatory response.⁵¹

§ Gastrointestinal Conditions: Inflammatory bowel illnesses (IBD), including ulcerative colitis and Crohn's disease, can benefit from targeted drug delivery via hydrogels that release anti-inflammatory drugs directly to the affected regions of the gut.⁵²

§ Cancer: Tumor-associated inflammation can be controlled by anti-inflammatory drug-loaded hydrogels, potentially reducing the progression of cancer while also minimizing side effects from systemic chemotherapy.⁵³

Case Studies or Examples of Successful Formulations:

§ Ibuprofen-loaded Nanosponges: Developed ibuprofen-loaded nanosponges incorporated into hydrogels to treat inflammation in an animal model of paw edema. The formulation showed sustained release of the drug, providing a long-lasting anti-inflammatory effect, and was more effective than free ibuprofen in reducing paw swelling.⁵⁴

§ Curcumin-loaded Nanosponges: In another example, curcumin, a well-known anti-inflammatory agent, was encapsulated into β-cyclodextrin-based nanosponges and incorporated into hydrogels. The formulation was shown to reduce inflammatory markers and enhance tissue repair in a chronic inflammatory rat model.⁵⁵

CONCLUSION:

Nanosponge-loaded hydrogels emerge as a revolutionary approach in drug delivery, particularly for anti-inflammatory therapies. By merging the solubility-enhancing properties of nanosponges with the biocompatible, controlled-release characteristics of hydrogels, this system addresses challenges like systemic side effects and poor bioavailability. Characterization and therapeutic evaluations underscore their potential in delivering targeted, sustained treatment for conditions like arthritis, psoriasis, and inflammatory bowel diseases. The integration not only improves therapeutic outcomes but also opens avenues for broader biomedical applications.

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Received on 24.04.2025 Revised on 14.08.2025

Accepted on 28.10.2025 Published on 22.01.2026

Available online from January 29, 2026

Asian J. Pharm. Res. 2026; 16(1):27-32.

DOI: 10.52711/2231-5691.2026.00004

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.

Synthesis methods	Description	Materials used	References
Crosslinking Cyclodextrins	Cyclodextrins are crosslinked with agents to create a porous network. The resulting nanosponges can have hydrophilic or hydrophobic characteristics depending on the crosslinker and cyclodextrin type.	Cyclodextrins, Epichlorohydrin, Diphenyl Carbonate, Carbonyldiimidazole	13
Polymerization Techniques	Nanosponges are synthesized through radical or condensation polymerization, forming stable networks with desirable mechanical and chemical properties.	Polyester, Polyurethanes, Hyper-crosslinked Polystyrene	14
Green Synthesis	Environmentally friendly methods utilize biopolymers and natural crosslinkers to reduce toxicity and environmental impact.	Biopolymers, Citric Acid, Sodium Trimetaphosphate	14

Sr No	Drug	Carrier	Inference	Reference
1	Doxorubicin	Nanosponges based on carbon quantum dots that contain polyethylene glycol and hydrazine	The combination dissolved in the tumour microenvironment for theranostic action, and the nanosponges exhibited very little drug leakage.	56
2	Carboplatin	Hydrogel of nanosponges based on ethylcellulose	The hydrogel based on nanosponge offered a prolonged release.	57
3	Temoporfin	The β-cyclodextrin is hypercrosslinked.	It demonstrated improved penetration and even dispersion of temoporfin in spheroids, as well as comparable photodynamic treatment to a free medication.	58
4	Celecoxib	Hydrogel based on β-cyclodextrin and NN-methylene bisacrylamide nanosponge	Celecoxib's solubility and bioavailability were increased by 30 to 65 times.	59
5	Econazole nitrate	N, N-Carbonyl diimidazole, β-cyclodextrin	Econazole nitrate-loaded hydrogel nanosponges have better release and are more effective at preventing fungal infections.	60