Introduction to Chemoradiotherapy-Induced Oral Mucositis

Chemoradiotherapy-induced oral mucositis (OM) is a prevalent and debilitating complication experienced by patients undergoing cancer treatments. This condition is characterized by inflammation and ulceration of the oral mucosa, leading to significant pain, difficulty in swallowing, and an overall decline in quality of life. The pathogenesis of OM is multifaceted, involving direct cellular damage from radiation and chemotherapeutic agents, as well as inflammatory responses that can exacerbate tissue injury (Wei et al., 2025). Approximately 40-90% of patients undergoing chemotherapy or chemoradiotherapy develop OM, highlighting the urgent need for effective therapeutic strategies to manage this condition (Wei et al., 2025).

Current treatment options for OM primarily focus on symptom relief and management, including the use of topical analgesics, anti-inflammatory agents, and antimicrobial therapies. However, these treatments often provide inadequate relief and do not address the underlying pathophysiological processes (Wei et al., 2025). Thus, innovative approaches are necessary to enhance mucosal healing and reduce the severity of OM.

Recent advancements in nanomedicine have opened new avenues for targeted drug delivery systems capable of improving the therapeutic efficacy of traditional treatments. Exosome-like nanovesicles (ENs), derived from natural sources, have gained attention for their role in drug delivery due to their biocompatibility and ability to mimic cellular components involved in wound healing (Wei et al., 2025). This article explores the potential of oridonin-loaded ENs in promoting wound healing in chemoradiotherapy-induced OM through a semi-interpenetrating network hydrogel system.

Role of Exosome-Like Nanovesicles in Drug Delivery

Exosome-like nanovesicles (ENs) represent a novel and promising drug delivery system. These nanoscale vesicles are naturally occurring extracellular vesicles that facilitate intercellular communication and play crucial roles in various biological processes. ENs can encapsulate a wide range of therapeutic agents, including proteins, nucleic acids, and small molecules, protecting them from degradation and enhancing their bioavailability (Wei et al., 2025).

The unique structure of ENs, characterized by a lipid bilayer, allows for the efficient delivery of encapsulated drugs to targeted tissues, thereby minimizing off-target effects. This property is particularly beneficial in the treatment of oral mucositis, as it enhances the localized delivery of therapeutic agents directly to the affected mucosal tissues (Wei et al., 2025). Furthermore, the inherent biocompatibility of ENs reduces the risk of adverse reactions, making them an ideal candidate for drug delivery in clinical applications.

In the context of chemoradiotherapy-induced OM, ENs can be engineered to incorporate specific therapeutic agents, such as oridonin, a natural compound known for its anti-inflammatory and antibacterial properties. The encapsulation of oridonin within ENs not only enhances its solubility and stability but also allows for a controlled release of the drug, improving its therapeutic efficacy and reducing the frequency of administration (Wei et al., 2025).

Characteristics and Benefits of Oridonin-Loaded Nanovesicles

Oridonin, a bioactive compound extracted from the traditional Chinese medicinal herb Rabdosia rubescens, has demonstrated significant anti-inflammatory and antibacterial effects. However, its clinical application is hindered by poor solubility and bioavailability. By integrating oridonin into ENs, researchers have developed a novel therapeutic approach that may overcome these limitations (Wei et al., 2025).

Encapsulation Efficiency and Drug Release Profile

The encapsulation efficiency (EE) of oridonin in ENs has been reported to be as high as 76.4%, indicating that a substantial proportion of the drug can be effectively loaded into the nanovesicles (Wei et al., 2025). The drug release profile of oridonin-loaded ENs demonstrates a sustained release pattern, which is crucial for maintaining therapeutic levels of the drug over an extended period. This prolonged release can lead to enhanced wound healing by ensuring that anti-inflammatory and antibacterial effects are consistently delivered to the site of injury (Wei et al., 2025).

Biocompatibility and Antibacterial Properties

The biocompatibility of oridonin-loaded ENs has been evaluated through various assays, demonstrating minimal cytotoxic effects on cell lines, such as L929 fibroblasts. Additionally, ENs have shown promising antibacterial properties against common oral pathogens, which is essential in preventing secondary infections during the healing process (Wei et al., 2025). The combination of oridonin’s intrinsic pharmacological activities and the drug delivery capabilities of ENs creates a synergistic effect that enhances the overall therapeutic outcome for patients suffering from OM.

Biocompatibility and Antibacterial Properties of Hydrogel Systems

Hydrogel systems represent a versatile and effective approach for wound healing applications. The semi-interpenetrating network (semi-IPN) hydrogel is particularly notable for its ability to provide a moist environment, which is conducive to tissue repair and regeneration. The incorporation of oridonin-loaded ENs within the semi-IPN hydrogel enhances its healing properties while simultaneously prolonging the release of therapeutic agents.

Properties of Semi-IPN Hydrogel

Semi-IPN hydrogels are characterized by their three-dimensional cross-linked structures, which allow for significant water retention while providing mechanical stability. This unique property of semi-IPN hydrogels not only aids in creating a suitable environment for cell proliferation and migration but also protects the encapsulated drug from degradation (Wei et al., 2025). The hydrogel can adhere effectively to the mucosal surfaces, thereby ensuring localized delivery of the embedded ENs and oridonin, which is crucial for the treatment of OM.

In Vivo Efficacy of Hydrogel Systems

In vivo studies have demonstrated that the application of oridonin-loaded ENs within a semi-IPN hydrogel significantly promotes wound healing in chemoradiotherapy-induced OM models. Histological analyses reveal increased collagen deposition, reduced inflammation, and accelerated mucosal regeneration compared to control groups (Wei et al., 2025). The hydrogel system has been shown to target the NLRP3 inflammasome pathway, thus modulating the inflammatory response and enhancing the healing process (Wei et al., 2025).

Mechanisms of Action for Enhanced Wound Healing Strategies

The mechanisms through which oridonin-loaded ENs within a semi-IPN hydrogel enhance wound healing in chemoradiotherapy-induced OM can be attributed to several key factors.

Anti-Inflammatory Effects

Oridonin exerts potent anti-inflammatory effects by inhibiting the activation of pro-inflammatory cytokines and pathways, including the NLRP3 inflammasome (Wei et al., 2025). By targeting these pathways, oridonin-loaded ENs can effectively modulate the inflammatory response, reducing tissue damage and promoting a conducive environment for healing.

Promotion of Cell Migration and Proliferation

The presence of oridonin within ENs has been shown to enhance the migratory and proliferative capacities of fibroblasts, which are essential for wound healing (Wei et al., 2025). The sustained release of oridonin from the hydrogel ensures that fibroblasts receive continuous exposure to the drug, thereby promoting tissue regeneration and collagen synthesis.

Enhanced Angiogenesis

Additionally, the hydrogel system has been linked to improved angiogenesis, which is critical for providing oxygen and nutrients to the healing tissues. Enhanced blood supply facilitates the repair process, further contributing to faster recovery from chemoradiotherapy-induced OM (Wei et al., 2025).

Conclusion

The integration of oridonin-loaded exosome-like nanovesicles within a semi-IPN hydrogel represents a promising therapeutic approach for enhancing wound healing in patients suffering from chemoradiotherapy-induced oral mucositis. This innovative strategy not only addresses the limitations associated with the solubility and bioavailability of oridonin but also leverages the unique properties of ENs and hydrogels to provide sustained drug release and localized treatment. By targeting key inflammatory pathways and promoting cellular activities essential for tissue repair, this approach has the potential to significantly improve the quality of life for patients undergoing cancer treatments.

References

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Wei, X., Wang, M., Dong, X., He, Y., & Chen, H. (2025). Internal-External Homologous Drug-Loaded Exosome-Like Nanovesicles Released from Semi-IPN Hydrogel Enhancing Wound Healing of Chemoradiotherapy-Induced Oral Mucositis. International Journal of Nanomedicine. Retrieved from https://doi.org/10.2147/IJN.S508530