Effectiveness of Curcumin Nanoparticles in the Management of Oral Mucositis: A Systematic Review

Effectiveness of Curcumin Nanoparticles in the Management of Oral Mucositis: A Systematic Review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Effectiveness of Curcumin Nanoparticles in the Management of Oral Mucositis: A Systematic Review Sinduja Palati, Monal Yuwanati, Adetola Emmanuel Babalola, Victor Adeyanju Somoye, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8470615/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Oral mucositis is a painful oral condition with diverse etiology and limited effective treatment modalities. Curcumin, a natural compound from curcumin longa, has anti-inflammatory and healing properties but is poorly absorbed by the body. A few studies have reported how curcumin nanoparticles (CNPs) have been created to solve this problem and improve effectiveness. This study reviewed how well CNPs work in treating oral mucositis. Methods We followed PRISMA guidelines and searched major databases for clinical studies using curcumin nanoparticles to treat oral mucositis. Only human studies comparing CNPs to placebos or standard treatments were included. Two reviewers independently selected and analyzed studies. The risk of bias and quality of the studies were assessed using Cochrane’s Risk of Bias tool 2 for randomized controlled trials. Results Two clinical trials from Iran were included. One trial used nano-curcumin capsules, and the other trial combined capsules with mouthwash. However, both studies showed that CNPs reduced the severity of mucositis, delayed its onset, and assist in mucosal healing. Patients using CNPs had less pain and fewer ulcers by the third week. In additon, CNPs did not had any serious side effects. Conclusion CNPs was found a safe and effective option for reducing the severity and pain of oral mucositis. Although the findings are promising, more studies in different countries are needed to confirm these results. Dentistry Oncology Curcumin nanoparticles oral mucositis radiotherapy nanotechnology pain relief mouth ulcers Figures Figure 1 Figure 2 Introduction Oral mucositis, characterized by painful inflammation and ulceration of the oral tissues, is a common and often unavoidable complication in patients, especially undergoing chemoradiotherapy for head and neck cancers [ 1 , 2 ]. Affecting up to 80% of individuals [ 2 , 3 ], it not only causes significant discomfort and impairs nutrition and quality of life, but also disrupts treatment, sometimes requiring dose reductions or interruptions that may reduce treatment success [ 4 ]. Despite ongoing efforts, a universally effective therapy for oral mucositis remains unavailable. Patients are commonly managed with palliative interventions such as mouthwashes, cryotherapy, or photobiomodulation, which may offer symptomatic relief but lack consistent efficacy in preventing or repairing mucosal damage [ 5 ]. Curcumin, a bright yellow compound extracted from Curcuma longa (turmeric) [ 6 ], has drawn significant interest. It is widely recognized for its anti-inflammatory, antioxidant, antimicrobial, and healing properties [ 6 – 8 ]. Laboratory and animal studies have shown that curcumin reduces inflammation by blocking the NF-κB (Nuclear Factor kappa-light chain) pathway, removes harmful free radicals, and promotes the healing of mucosal tissues by stimulating growth factors like EGF. It also helps prevent secondary infections in damaged tissues [ 8 ]. These combined actions make curcumin a promising candidate for managing oral mucositis. However, its effectiveness in humans has been limited because the body absorbs it poorly and breaks it down quickly, a problem known as poor bioavailability [ 9 ]. To address this limitation, nano-formulations, including nanomicellar and nanoparticle curcumin, have been developed [ 10 ]. These systems enhance solubility, protect the compound from rapid metabolism, and facilitate improved tissue targeting [ 6 , 10 ]. Clinical investigations confirm their efficacy. For instance, nanomicellar curcumin capsules (80 mg twice daily) significantly reduced the severity of oral mucositis and pain over seven weeks in head and neck cancer patients receiving chemotherapy and/or radiotherapy [ 11 ]. Similarly, a 0.1% curcumin nanoparticle mouthwash delayed mucositis onset, with variable impact on incidence [ 12 , 13 ]. Additional evidence shows that both mouthwash and nanocapsules can reduce oral discomfort and ulceration, with a significant portion of patients remaining ulcer-free after three weeks [ 13 ]. Finally, curcumin across various formulations (mouthwashes, gels, capsules, and nano‑curcumin) significantly improves outcomes in oral mucositis, reducing pain and lesion severity. However, despite the potential of curcumin, the evidence remains scattered and limited. This review therefore, provides a timely synthesis on the effect of CNPs on oral mucositis. Materials and Methods: 2.1 Protocol and Registration This systematic review was developed following the PRISMA guidelines (Appendix I) [ 14 ]. The protocol was registered with PROSPERO under the registration number CRD420251045148. 2.2 Eligibility Criteria This systematic review considered studies eligible if they evaluated the impact of curcumin nanoparticles (CNPs) in patients diagnosed with oral mucositis (OM). Only studies comparing CNPs to placebo, standard of care, or other curcumin formulation. Additionally, studies reporting the clinical outcomes such as mucositis severity, duration, pain scores, or onset time. Eligible studies included randomised controlled trials, non-randomised interventional studies, and observational designs that reported relevant outcome measures. Studies were excluded if they focused solely on curcumin as the treatment and not the nanoparticles, lacked original data (such as reviews, commentaries, or conference abstracts), or failed to report extractable outcome data. To ensure a comprehensive and inclusive review, no restrictions were placed on language, year of publication, geographic location, or sample size. 2.3 Search Strategy A thorough and systematic search of the literature was conducted using several major electronic databases, including PubMed, Web of Science, Scopus and Cochrane. To further minimise the risk of publication bias, grey literature was actively explored. In addition, the reference lists of all included studies were carefully reviewed to identify additional relevant publications that may not have been captured through the initial database search. The search strategy was designed to be both sensitive and comprehensive. It utilised a combination of MeSH and free-text keywords to encompass all relevant terminologies associated with the condition and the biomarker of interest. The final search expression included terms such as “(("Curcumin" OR "Turmeric" OR "Curcuminoids" OR "Diferuloylmethane") AND ("Nanoparticles" OR "Nanotechnology" OR "Nanocurcumin" OR "Nanoformulations" OR "Nanospheres") AND ("Oral Mucositis" OR "Oral Inflammation" OR "Oral Ulcers" OR "Oral Lesions" OR "Stomatitis" OR "Chemotherapy-Induced Mucositis" OR "Radiotherapy-Induced Mucositis"))”. No filters were applied to restrict results based on date, language, or article type. Additional articles were identified by manually searching the bibliographies of included studies, key oral pathology journals, and clinical trial registries. 2.4 Study Selection All retrieved references were imported into the Rayyan online platform for systematic review screening [ 15 ]. Two reviewers independently screened the titles and abstracts of all identified studies based on predefined eligibility criteria. Full-text articles of potentially relevant studies were then retrieved and assessed for final inclusion. Any disagreements between the reviewers were resolved through discussion, and a third reviewer was consulted in cases where consensus could not be reached. The PRISMA 2020 flowchart was used to document the study selection process, including reasons for exclusion at each stage ( Fig. 1 ) . 2.5 Data Extraction Data extraction was performed independently by two reviewers using a standardised and pre-tested data collection form. For each included study, data were collected on the study title, first author, year of publication, journal name, country of origin, funding status, and study design. Participants' details, such as sample size, age, sex distribution, diagnosis of Oral mucositis, severity, onset, and duration were recorded. Intervention characteristics, including the experimental drug, comparator drug, dose, route of administration, duration were extracted. The primary outcome was the reduction in the severity of the clinical symptoms (Pain levels (VAS), inflammation, redness) and duration, and secondary outcomes included clinical improvements in symptoms associated with oral mucositis (ulceration, difficulty in swallowing), incidence of adverse side effects and duration of treatment. Data on study limitations, follow-up duration, withdrawals, and completeness of outcome reporting were also noted. In cases where the required data was unclear or missing, attempts were made to contact the original study authors. Discrepancies in data extraction were resolved through discussion or arbitration by a third reviewer. 2.6 Risk of Bias analysis The Cochrane tool (RoB2) was used to assess the risk of bias, while publication bias was evaluated using Egger’s weighted regression test. If publication bias was detected, the trim-and-fill method was used to estimate its potential impact on the overall effect sizes. 2.7 Data Synthesis and Statistical Analysis For continuous outcomes (Pain score, inflammation and redness), we will compute mean differences, along with 95% confidence intervals (CIs). Given the anticipated considerable between-study heterogeneity, we will utilize a random-effects model with 95% confidence interval. The Sidik–Jonkman estimator with Hartaung-Knapp (HK) adjustments will be employed to pool effect sizes. Between-study heterogeneity will be assessed using Cochran’s Q test, I square test, and prediction intervals. Meta-regression and subgroup analyses will be performed to investigate potential sources of heterogeneity. The meta- regression analysis will be carried out with a random-effects model. Furthermore, subgroup interactions will be tested with the chi-square test. Sensitivity analyses will be performed initially using the leave-one-out approach to assess the influence of individual trials on the overall effect estimate. Results 3.1 Study Characteristics A total of two randomized controlled trials (RCTs) met the inclusion criteria for this systematic review (Fig. 1 ). Both studies were conducted in Iran and evaluated the efficacy of curcumin-based nanoparticle formulations in the prevention or treatment of radiotherapy-induced oral mucositis (OM) in patients with head and neck cancers. A summary of individual study characteristics is provided in Table 1 (Appendix II ). The study by Delavarian et al. (2019) included 32 patients (19 males and 13 females), with a mean age of 62.18 ± 15.07 years in the treatment group and 55.87 ± 15.33 years in the control group [ 16 ]. The study employed a double-blind, placebo-controlled design, with participants receiving oral nano micellar curcumin (SinaCurcumin®) at a dose of 80 mg/day. The comparator was a placebo tablet containing lactose. The intervention began on the first day of radiotherapy and continued for six weeks, with assessments conducted on days 7, 14, 21, 28, 35, and 42 during which the mucositis was assessed [ 16 ]. The second study, by Ramezani et al. (2023), included 45 patients (23 males and 14 females) aged 53.36 ± 15.99 years, all diagnosed with grades 1 to 3 Oral Mucositis [ 13 ]. Participants were randomized to receive either curcumin mouthwash (0.1% w/v), curcumin nano capsules (40 mg curcuminoids), or a placebo mouthwash over a three-week period, with weekly follow-ups [ 13 ]. The study was single-blinded, with patients unaware of the treatment received. Both studies utilized standard clinical mucositis grading systems: the WHO oral mucositis grading scale [ 17 ], with the National Rating Scale (NRS) additionally applied in the Ramezani et al. study [ 13 ]. 3.2 Formulation and Dosage Comparison Although both trials used curcumin nanoparticles, they differed in how they were delivered. Delavarian et al. used a commercial nano micellar curcumin (SinaCurcumin®) taken orally at 80 mg/day throughout radiotherapy, aiming for consistent systemic absorption [ 16 ]. Ramezani et al., on the other hand, combined topical curcumin mouthwash with oral nano capsules, offering both local and systemic action [ 13 ]. Both approaches showed positive outcomes, suggesting that curcumin is effective in various nano formulations and delivery routes [ 13 , 16 ]. 3.3 Efficacy in Reducing Oral Mucositis Severity Both studies reported that curcumin nanoparticle-based interventions were effective in reducing the severity and progression of oral mucositis compared to placebo controls [ 13 , 16 ]. In Delavarian et al., oral administration of nano micellar curcumin led to lower mucositis grades at each evaluation point compared to placebo [ 16 ]. By day 14, most patients in the treatment group maintained at Grade 0 or Grade 1, whereas the placebo group showed a steady progression to Grade 2 and Grade 3 mucositis by week 3 and beyond [ 16 ]. Specifically, none of the study group patients developed grade 1 mucositis after 1 week, while 37.5% of the control group did. After 2 weeks, only 25% of the study group developed grade 1, compared to 50% in the control group [ 16 ]. Although mucositis developed in both groups, the onset was delayed, and the severity was reduced in the curcumin group [ 16 ]. In Ramezani et al., both curcumin-treated groups (mouthwash and nano capsule) demonstrated a significant reduction in mucositis scores compared to placebo by week 3 (p < 0.001).(13) In weeks 1 and 2, no significant differences were observed among the three groups; however, the therapeutic effect became marked at the third week [ 13 ]. This highlights the time-dependent efficacy of curcumin formulations in mucosal recovery. 3.4 Pain Relief and Symptom Management Pain levels were assessed using the Visual Analog Scale (VAS) or Numerical Rating Scale (NRS). In Ramezani et al., although weeks 1 and 2 did not show significant intergroup differences, by week 3, the VAS scores in both curcumin-treated groups were significantly lower than the placebo group (p < 0.001), showing a notable symptom relief on prolonged usage of the medication [ 13 ]. Delavarian et al. did not report detailed VAS pain scores, and the study primarily focused on the prevention and reduction of OM severity, the observed improvements directly translate into significant pain relief and better symptom management for patients [ 16 ]. By delaying onset, reducing severity, and improving food intake, nanomicelle curcumin helps alleviate the painful and debilitating effects of oral mucositis, thereby improving the patient's quality of life during critical cancer treatment. 3.5 Inflammation, Redness, and Tissue Healing Both studies noted reduction in inflammation and erythema, although not quantified using biochemical markers. Delavarian et al. categorized mucositis severity based on presence of erythema, pseudomembrane formation, and ulceration. Participants receiving nanocurcumin maintained lower grades, with minimal or no progression to confluent pseudomembrane or necrosis[ 16 ]. The study group had a lower grade of mucositis compared to the control group throughout the treatment. For instance, grade 3 mucositis was observed in 50% of the control group after 3 weeks, while only 33.3% of the study group reached this grade after 4 weeks [ 16 ]. At the end of the radiation therapy course, the NCI-CTC v.2 scores indicated that the study group had a mean score of 1 ± 0.84, while the control group had a mean score of 1.78 ± 0.42. This difference was statistically significant (P = 0.005) [ 16 ]. Ramezani et al. reported clinical resolution of inflammation and redness by the end of three weeks in the curcumin groups, with mucosal surfaces appearing near normal in most patients, while persistent erythema and ulceration were noted in the placebo group [ 13 ]. 3.6 Safety and Tolerability No serious adverse events were reported in either study. Participants tolerated both oral and topical curcumin formulations well, with no discontinuation due to side effects[ 13 , 16 ]. This reinforces the safety profile of curcumin nanoparticles, making them suitable for extended use during chemoradiotherapy. 3.7 Follow-up and Clinical Impact The follow-up period in Delavarian et al. extended across six weeks, aligning with the standard course of radiotherapy [ 16 ], while Ramezani et al. followed patients for three weeks post-intervention [ 13 ]. Both studies concluded that curcumin nanoparticles can effectively reduce severity, delay the onset, and accelerate the healing of oral mucositis, with potential for integration into routine oncology care[ 13 , 16 ]. 3.8 Risk of Bias Both studies [ 13 , 16 ] were of low risk, however Ramezani et al study have some concerns due to missing data (Fig. 2 ). Discussion This systematic review evaluated the effectiveness of curcumin nanoparticles in the prevention and management of oral mucositis in patients undergoing radiotherapy for head and neck cancers. The findings from the two included randomized controlled trials demonstrate that curcumin nanoparticles offer a promising therapeutic option having shown delayed onset of oral mucositis with significant reduction in severity and improved tissue healing compared to placebo [ 13 , 16 ]. These results support the growing body of evidence which suggests that nano-formulated curcumin has enhanced clinical efficacy compared to traditional curcumin preparations, primarily due to improved bioavailability and targeted tissue delivery [ 18 ]. The results of this systematic review, encompassing two randomized controlled trials, provide compelling evidence that curcumin nanoparticle-based interventions are a safe and effective strategy for managing radiotherapy-induced oral mucositis. The findings consistently demonstrate a significant reduction in mucositis severity and pain, delayed onset, and improved tissue healing compared to placebo, confirming the therapeutic potential of this novel formulation [ 13 , 16 ]. A key strength of the reviewed studies is their focus on nanocurcumin, which addresses the critical issue of poor bioavailability that has historically limited the clinical application of standard curcumin [ 19 ]. The distinct delivery methods employed, oral nano micellar capsules in the study by Delavarian et al. and a combination of topical mouthwash and oral nano capsules in Ramezani et al., both yielded positive outcomes [ 13 , 16 ]. This suggests that the enhanced absorption and targeted delivery provided by nanotechnological approaches are central to the observed efficacy. The fact that both systemic (oral capsules) and local (mouthwash) administrations were successful opens the door for a flexible, multi-modal approach to treatment, where systemic effects can target underlying inflammatory pathways while topical applications provide direct relief to mucosal surfaces [ 20 ]. Another important observation is the consistently lower mucositis severity scores in the treatment groups. For example, Delavarian et al. noted that those receiving the nano micellar capsules had significantly milder mucositis grades throughout the six-week treatment window, and these differences were statistically meaningful by the end of the study [ 16 ]. Similarly, Ramezani et al. reported a clear improvement by the third week in the curcumin groups [ 13 ]. These results imply that curcumin nanoparticles not only slow the onset of mucositis but may also promote quicker recovery once symptoms develop. The delayed onset of mucositis observed by Delavarian et al. is also a critical clinical benefit, as it implies that patients can maintain nutritional intake with reduced likelihood of treatment interruptions. In the same vein, pain relief, which is a primary concern for patients with oral mucositis, was also significantly improved by the nanocurcumin interventions. Ramezani et al.'s findings that both curcumin groups had significantly lower VAS scores by week 3 highlight the clinical relevance of this treatment. While Delavarian et al. did not report detailed pain scores, the observed improvements in mucositis severity, which is directly correlated with pain, suggest a positive impact on patient comfort and quality of life. This is further supported by the noted improvements in symptoms like difficulty swallowing [ 13 , 16 ]. The safety and tolerability of curcumin nanoparticles, as highlighted by both studies, are major advantages [ 13 , 16 ].With no serious adverse events and no withdrawals due to side effects, nanocurcumin emerges as a well-tolerated option for a patient population already burdened by the side effects of cancer treatment. This excellent safety profile, coupled with its demonstrated efficacy, makes it a highly attractive candidate for integration into standard supportive care protocols. However, despite these strengths, the review has several limitations. The evidence base is restricted to just two studies, both conducted in Iran. While the designs of the trials were rigorous, including a double-blind, placebo-controlled trial, their relatively small sample sizes and limited geographic scope may affect the applicability of the results to wider populations. Also, the lack of detailed reporting on pain scores in one of the studies also represents a gap in the available evidence. Finally, the differences in formulation like micellar capsules, mouthwash and nano capsules, and treatment duration across the studies, while highlighting the versatility of nanocurcumin, make direct comparisons and meta-analysis challenging. Future research should aim to address these limitations. Larger multi-centre international randomized controlled trials are needed to confirm these findings across diverse populations and cancer types. Studies should also standardize the reporting of outcomes, particularly pain scores, to allow for more robust statistical analysis. Additionally, head-to-head comparisons of different nanocurcumin formulations could provide valuable insights into optimal delivery methods. Finally, investigations into the precise molecular mechanisms of nanocurcumin in human subjects, beyond its established anti-inflammatory and antioxidant properties, would further strengthen the evidence base for its clinical use. Conclusion This systematic review provides consistent evidence that curcumin nanoparticle-based formulations are a safe and effective intervention for the prevention and management of oral mucositis. The benefits of CNPs include; delayed onset of mucositis, reduction in pain severity, mucosal healing, and improved patient comfort, with no reported serious adverse effects. Nevertheless, the limited number of available studies, small sample sizes, necessitate caution in generalizing results. Future studies should look toward designing large-scale, multi-center trials with standardized outcome measures and direct comparisons of various nanocurcumin delivery systems are warranted to establish optimal protocols and confirm the broader applicability of these promising findings. Abbreviations CNP: Curcumin NanoParticle PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses ROB: Risk Of Bias NF-κB: Nuclear Factor kappa-light MeSH: Medical Subject Headings OM: Oral Mucositis GRADE: Grading of Recommendations Assessment, Development, and Evaluation VAS: Visual Assessment Scale NRS: Numerical Rating Scale CI: Confidence Interval Declarations Acknowledgments: None Declaration of conflicting interest: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Funding statement: None Ethical approval and informed consent statements: Not Applicable Data availability statement: All data generated or analyzed during this study are included in this published article and its supplementary information files. References Karlsson C, Bohm N, Andersson JS, Finizia C, Almståhl A (2024) Prospective study on health-related quality of life, oral mucositis and oral health on during treatment of head and neck cancer. BMC Oral Health 24(1):697. https://doi.org/10.1186/s12903-024-04466-5 Pacheco R, Cavacas MA, Mascarenhas P, Oliveira P, Zagalo C Incidence of oral mucositis in patients undergoing head and neck cancer treatment: Systematic review and meta-analysis. InMedical Sciences Forum 2021 Jul 21 (Vol. 5, No. 1, p. 23). MDPI. https://doi.org/10.3390/msf2021005023 Iovoli AJ, Turecki L, Qiu ML, Khan M, Smith K, Yu H, Ma SJ, Farrugia MK, Singh AK (2023) Severe oral mucositis after intensity-modulated radiation therapy for head and neck cancer. JAMA Netw open 6(10):e2337265. https://doi.org/10.1001/jamanetworkopen.2023.37265 Pai RR, Ongole R, Banerjee S (2025) Retrospective evaluation of oral complications following radiotherapy and chemoradiation in patients with head and neck Cancer. Sci Rep 15(1):24726. https://doi.org/10.1038/s41598-025-10598-7 Lalla RV, Bowen J, Barasch A, Elting L, Epstein J, Keefe DM, McGuire DB, Migliorati C, Nicolatou-Galitis O, Peterson DE, Raber‐Durlacher JE (2014) MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer 120(10):1453–1461. https://doi.org/10.1002/cncr.28592 Tagde P, Tagde P, Islam F, Tagde S, Shah M, Hussain ZD, Rahman MH, Najda A, Alanazi IS, Germoush MO, Mohamed HR (2021) The multifaceted role of curcumin in advanced nanocurcumin form in the treatment and management of chronic disorders. Molecules 26(23):7109. https://doi.org/10.3390/molecules26237109 Aggarwal BB, Sundaram C, Malani N, Ichikawa H Curcumin: the Indian solid gold. The molecular targets and therapeutic uses of curcumin in health and disease. 2007 Jan 1:1–75. https://doi.org/10.1007/978-0-387-46401-5_1 Hewlings SJ, Kalman DS, Curcumin (2017) A review of its effects on human health. Foods 6(10):92. https://doi.org/10.3390/foods6100092 Lopresti AL (2018) The problem of curcumin and its bioavailability: could its gastrointestinal influence contribute to its overall health-enhancing effects? Adv Nutr 9(1):41–50. 10.1093/advances/nmx011 Mohanty C, Das M, Sahoo SK (2012) Emerging role of nanocarriers to increase the solubility and bioavailability of curcumin. Expert Opin Drug Deliv 9(11):1347–1364. https://doi.org/10.1517/17425247.2012.724676 Kia SJ, Basirat M, Saedi HS, Arab SA (2021) Effects of nanomicelle curcumin capsules on prevention and treatment of oral mucosits in patients under chemotherapy with or without head and neck radiotherapy: a randomized clinical trial. BMC Complement Med Ther 21(1):232. https://doi.org/10.1186/s12906-021-03400-4 Shah S, Rath H, Sharma G, Senapati SN, Mishra E (2020) Effectiveness of curcumin mouthwash on radiation-induced oral mucositis among head and neck cancer patients: A triple-blind, pilot randomised controlled trial. Indian J Dent Res 31(5):718–727. https://doi.org/10.4103/ijdr.ijdr_822_18 Ramezani V, Ghadirian S, Shabani M, Boroumand MA, Daneshvar R, Saghafi F (2023) Efficacy of curcumin for amelioration of radiotherapy-induced oral mucositis: a preliminary randomized controlled clinical trial. BMC Cancer 23(1):354. https://doi.org/10.1186/s12885-023-10730-8 Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Akl EA, Brennan SE, Chou R (2021) The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 372.doi:https://doi.org/10.1136/bmj.n71 Ouzzani M, Hammady H, Fedorowicz Z, Elmagarmid A (2016) Rayyan—a web and mobile app for systematic reviews. Syst reviews 5(1):210. https://doi.org/10.1186/s13643-016-0384-4 Delavarian Z, Pakfetrat A, Ghazi A, Jaafari MR, Homaei Shandiz F, Dalirsani Z, Mohammadpour AH, Rahimi HR (2019) Oral administration of nanomicelle curcumin in the prevention of radiotherapy-induced mucositis in head and neck cancers. Spec Care Dentist 39(2):166–172. 10.1111/scd.12358 Villa A, Vollemans M, De Moraes A, Sonis S (2021) Concordance of the WHO, RTOG, and CTCAE v4. 0 grading scales for the evaluation of oral mucositis associated with chemoradiation therapy for the treatment of oral and oropharyngeal cancers. Support Care Cancer 29(10):6061–6068. 10.1007/s00520-021-06177-x Dharman S, Maragathavalli G, Shanmugasundaram K, Shanmugam RK (2021) A systematic review and meta-analysis on the efficacy of curcumin/turmeric for the prevention and amelioration of radiotherapy/radiochemotherapy induced oral mucositis in head and neck cancer patients. Asian Pac J cancer prevention: APJCP 22(6):1671. 10.31557/APJCP.2021.22.6.1671 Tabanelli R, Brogi S, Calderone V (2021) Improving curcumin bioavailability: Current strategies and future perspectives. Pharmaceutics 13(10):1715. 10.3390/pharmaceutics13101715 Boroughani M, Moaveni AK, Hatami P, Mansoob Abasi N, Seyedoshohadaei SA, Pooladi A, Moradi Y, Rahimi Darehbagh R (2024) Nanocurcumin in cancer treatment: a comprehensive systematic review. Discover Oncol 15(1):515. 10.1007/s12672-024-01272-x Additional Declarations The authors declare no competing interests. Supplementary Files AppendixI.docx Supplementary Files Appendix I- PRISMA checklist AppendixII.docx Appendix II - Table 1: Characteristics of includes studies Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8470615","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":566683222,"identity":"6c8f1311-5531-4ec0-80bc-3604298d8ab8","order_by":0,"name":"Sinduja Palati","email":"","orcid":"","institution":"Department of Oral and Maxillofacial Pathology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, 600077, India.","correspondingAuthor":false,"prefix":"","firstName":"Sinduja","middleName":"","lastName":"Palati","suffix":""},{"id":566683368,"identity":"57f05430-a953-41b1-b94d-1ff88a2237f7","order_by":1,"name":"Monal Yuwanati","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2UlEQVRIiWNgGAWjYLCCBxU2PPbHG4AsAwsitSScSZNhOHMApEWCSC2JbYdtGG4kgJhEaNFt7z34IbEtjYdx5vOrG34USDDwt3cn4NViduZcskTCORseZumcsps9QIdJnDm7Ab+WGzkGEgllaTxs0jlpN3iAWgwkcglqMf6RwHaYh0fyTNrNP0RqMZNIaDvMIyHBfuw2cbacOWNmAQxkHgOeHLbbMgYSPIT9crzH+MaHCht7A/bjz26++WMjx9/ei18LEuAxAJPEKgcB9gekqB4Fo2AUjIIRBACDK0hjeWqxyAAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0001-9233-8292","institution":"Department of Oral and Maxillofacial Pathology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, 600077, India.","correspondingAuthor":true,"prefix":"","firstName":"Monal","middleName":"","lastName":"Yuwanati","suffix":""},{"id":566683369,"identity":"0b8f66bd-06d8-4c48-aaff-09069a6ff735","order_by":2,"name":"Adetola Emmanuel Babalola","email":"","orcid":"","institution":"Kornberg School of Dentistry, Temple University, Philadelphia., USA.","correspondingAuthor":false,"prefix":"","firstName":"Adetola","middleName":"Emmanuel","lastName":"Babalola","suffix":""},{"id":566683817,"identity":"ef576a07-b12a-43d7-be56-725c82f28a7d","order_by":3,"name":"Victor Adeyanju Somoye","email":"","orcid":"","institution":"Faculty of Dentistry, University of Ibadan, Ibadan, Nigeria,","correspondingAuthor":false,"prefix":"","firstName":"Victor","middleName":"Adeyanju","lastName":"Somoye","suffix":""},{"id":566683818,"identity":"190a37b7-8095-4c3a-b284-d6fc143e1ab7","order_by":4,"name":"Akinlolu Akinjola","email":"","orcid":"","institution":"University of Nigeria, Teaching Hospital, Ituku-Ozalla, Enugu","correspondingAuthor":false,"prefix":"","firstName":"Akinlolu","middleName":"","lastName":"Akinjola","suffix":""},{"id":566683819,"identity":"bdd1abc2-86ca-4d16-9e36-8dcc6bbf3627","order_by":5,"name":"Akhilanand Chaurasia","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0002-8356-9512","institution":"Department of Oral Medicine and Radiology, King George's Medical University, India","correspondingAuthor":true,"prefix":"","firstName":"Akhilanand","middleName":"","lastName":"Chaurasia","suffix":""}],"badges":[],"createdAt":"2025-12-29 08:06:02","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-8470615/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8470615/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":99607926,"identity":"b7921eb6-416e-4d52-96ea-50e9b6615f5b","added_by":"auto","created_at":"2026-01-06 11:52:09","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":43673,"visible":true,"origin":"","legend":"","description":"","filename":"Mainmanuscript.docx","url":"https://assets-eu.researchsquare.com/files/rs-8470615/v1/c205a00d1d5204cb788cf2d3.docx"},{"id":99607928,"identity":"1faf665a-c916-42fa-a4b7-318621acceed","added_by":"auto","created_at":"2026-01-06 11:52:09","extension":"json","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":342,"visible":true,"origin":"","legend":"","description":"","filename":"rs8470615.json","url":"https://assets-eu.researchsquare.com/files/rs-8470615/v1/2038565a10af5d3d0b87fdc2.json"},{"id":99607931,"identity":"7947e19f-5177-4371-b5ad-c2ef7e9b3397","added_by":"auto","created_at":"2026-01-06 11:52:09","extension":"xml","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":75301,"visible":true,"origin":"","legend":"","description":"","filename":"rs84706150enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-8470615/v1/4d32a3cfc40d6fd8fe8d689c.xml"},{"id":99607932,"identity":"76e32c81-f1bb-4b98-9180-ed8d15f69b07","added_by":"auto","created_at":"2026-01-06 11:52:09","extension":"xml","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":71670,"visible":true,"origin":"","legend":"","description":"","filename":"rs84706150structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8470615/v1/4cf8105b1211f001e44f9810.xml"},{"id":99792880,"identity":"91b381af-dfe0-4384-a236-379fab96febc","added_by":"auto","created_at":"2026-01-08 13:28:02","extension":"html","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":84171,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8470615/v1/76e8f251a03fd7dc950e67aa.html"},{"id":99793380,"identity":"923edd50-349c-4079-9ff1-be166a4c71cd","added_by":"auto","created_at":"2026-01-08 13:31:29","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":81370,"visible":true,"origin":"","legend":"\u003cp\u003eStudy selection, screening process (PRISMA Diagram)\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8470615/v1/0a6aa12ffaeb162726ee6297.jpg"},{"id":99607930,"identity":"e3610a15-e934-447a-95f2-c23ac51b8f8f","added_by":"auto","created_at":"2026-01-06 11:52:09","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":623603,"visible":true,"origin":"","legend":"\u003cp\u003eRisk of Bias assessment of included studies\u003c/p\u003e","description":"","filename":"Figur2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8470615/v1/04ba580781b8effca9863a88.jpeg"},{"id":99804149,"identity":"9f297fe0-c9a9-47c5-b590-95eaad9ee9d1","added_by":"auto","created_at":"2026-01-08 14:11:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1383868,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8470615/v1/2543a29e-fbf0-4926-ad8a-87dc181ea96d.pdf"},{"id":99607925,"identity":"340013df-ed4e-4e51-b6d3-7a98e04f7746","added_by":"auto","created_at":"2026-01-06 11:52:09","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":29014,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Files\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAppendix I- PRISMA checklist\u003c/p\u003e","description":"","filename":"AppendixI.docx","url":"https://assets-eu.researchsquare.com/files/rs-8470615/v1/a6d65968f5e9d0103f096977.docx"},{"id":99793323,"identity":"ed33094f-5c38-4a0d-96f0-9100e981e668","added_by":"auto","created_at":"2026-01-08 13:31:25","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":17283,"visible":true,"origin":"","legend":"\u003cp\u003eAppendix II - Table 1: Characteristics of includes studies\u003c/p\u003e","description":"","filename":"AppendixII.docx","url":"https://assets-eu.researchsquare.com/files/rs-8470615/v1/cddd6b62e75231b809527e24.docx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eEffectiveness of Curcumin Nanoparticles in the Management of Oral Mucositis: A Systematic Review\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eOral mucositis, characterized by painful inflammation and ulceration of the oral tissues, is a common and often unavoidable complication in patients, especially undergoing chemoradiotherapy for head and neck cancers [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Affecting up to 80% of individuals [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], it not only causes significant discomfort and impairs nutrition and quality of life, but also disrupts treatment, sometimes requiring dose reductions or interruptions that may reduce treatment success [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Despite ongoing efforts, a universally effective therapy for oral mucositis remains unavailable. Patients are commonly managed with palliative interventions such as mouthwashes, cryotherapy, or photobiomodulation, which may offer symptomatic relief but lack consistent efficacy in preventing or repairing mucosal damage [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCurcumin, a bright yellow compound extracted from Curcuma longa (turmeric) [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], has drawn significant interest. It is widely recognized for its anti-inflammatory, antioxidant, antimicrobial, and healing properties [\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Laboratory and animal studies have shown that curcumin reduces inflammation by blocking the NF-κB (Nuclear Factor kappa-light chain) pathway, removes harmful free radicals, and promotes the healing of mucosal tissues by stimulating growth factors like EGF. It also helps prevent secondary infections in damaged tissues [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. These combined actions make curcumin a promising candidate for managing oral mucositis. However, its effectiveness in humans has been limited because the body absorbs it poorly and breaks it down quickly, a problem known as poor bioavailability [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo address this limitation, nano-formulations, including nanomicellar and nanoparticle curcumin, have been developed [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. These systems enhance solubility, protect the compound from rapid metabolism, and facilitate improved tissue targeting [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Clinical investigations confirm their efficacy. For instance, nanomicellar curcumin capsules (80 mg twice daily) significantly reduced the severity of oral mucositis and pain over seven weeks in head and neck cancer patients receiving chemotherapy and/or radiotherapy [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Similarly, a 0.1% curcumin nanoparticle mouthwash delayed mucositis onset, with variable impact on incidence [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Additional evidence shows that both mouthwash and nanocapsules can reduce oral discomfort and ulceration, with a significant portion of patients remaining ulcer-free after three weeks [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFinally, curcumin across various formulations (mouthwashes, gels, capsules, and nano‑curcumin) significantly improves outcomes in oral mucositis, reducing pain and lesion severity. However, despite the potential of curcumin, the evidence remains scattered and limited. This review therefore, provides a timely synthesis on the effect of CNPs on oral mucositis.\u003c/p\u003e"},{"header":"Materials and Methods:","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Protocol and Registration\u003c/h2\u003e \u003cp\u003eThis systematic review was developed following the PRISMA guidelines (Appendix I) [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The protocol was registered with PROSPERO under the registration number CRD420251045148.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Eligibility Criteria\u003c/h2\u003e \u003cp\u003eThis systematic review considered studies eligible if they evaluated the impact of curcumin nanoparticles (CNPs) in patients diagnosed with oral mucositis (OM). Only studies comparing CNPs to placebo, standard of care, or other curcumin formulation. Additionally, studies reporting the clinical outcomes such as mucositis severity, duration, pain scores, or onset time. Eligible studies included randomised controlled trials, non-randomised interventional studies, and observational designs that reported relevant outcome measures. Studies were excluded if they focused solely on curcumin as the treatment and not the nanoparticles, lacked original data (such as reviews, commentaries, or conference abstracts), or failed to report extractable outcome data. To ensure a comprehensive and inclusive review, no restrictions were placed on language, year of publication, geographic location, or sample size.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Search Strategy\u003c/h2\u003e \u003cp\u003eA thorough and systematic search of the literature was conducted using several major electronic databases, including PubMed, Web of Science, Scopus and Cochrane. To further minimise the risk of publication bias, grey literature was actively explored. In addition, the reference lists of all included studies were carefully reviewed to identify additional relevant publications that may not have been captured through the initial database search.\u003c/p\u003e \u003cp\u003eThe search strategy was designed to be both sensitive and comprehensive. It utilised a combination of MeSH and free-text keywords to encompass all relevant terminologies associated with the condition and the biomarker of interest. The final search expression included terms such as \u0026ldquo;((\"Curcumin\" OR \"Turmeric\" OR \"Curcuminoids\" OR \"Diferuloylmethane\") AND (\"Nanoparticles\" OR \"Nanotechnology\" OR \"Nanocurcumin\" OR \"Nanoformulations\" OR \"Nanospheres\") AND (\"Oral Mucositis\" OR \"Oral Inflammation\" OR \"Oral Ulcers\" OR \"Oral Lesions\" OR \"Stomatitis\" OR \"Chemotherapy-Induced Mucositis\" OR \"Radiotherapy-Induced Mucositis\"))\u0026rdquo;. No filters were applied to restrict results based on date, language, or article type. Additional articles were identified by manually searching the bibliographies of included studies, key oral pathology journals, and clinical trial registries.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Study Selection\u003c/h2\u003e \u003cp\u003eAll retrieved references were imported into the Rayyan online platform for systematic review screening [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Two reviewers independently screened the titles and abstracts of all identified studies based on predefined eligibility criteria. Full-text articles of potentially relevant studies were then retrieved and assessed for final inclusion. Any disagreements between the reviewers were resolved through discussion, and a third reviewer was consulted in cases where consensus could not be reached. The PRISMA 2020 flowchart was used to document the study selection process, including reasons for exclusion at each stage \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5 Data Extraction\u003c/h2\u003e \u003cp\u003eData extraction was performed independently by two reviewers using a standardised and pre-tested data collection form. For each included study, data were collected on the study title, first author, year of publication, journal name, country of origin, funding status, and study design.\u003c/p\u003e \u003cp\u003eParticipants' details, such as sample size, age, sex distribution, diagnosis of Oral mucositis, severity, onset, and duration were recorded. Intervention characteristics, including the experimental drug, comparator drug, dose, route of administration, duration were extracted. The primary outcome was the reduction in the severity of the clinical symptoms (Pain levels (VAS), inflammation, redness) and duration, and secondary outcomes included clinical improvements in symptoms associated with oral mucositis (ulceration, difficulty in swallowing), incidence of adverse side effects and duration of treatment.\u003c/p\u003e \u003cp\u003eData on study limitations, follow-up duration, withdrawals, and completeness of outcome reporting were also noted. In cases where the required data was unclear or missing, attempts were made to contact the original study authors. Discrepancies in data extraction were resolved through discussion or arbitration by a third reviewer.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e2.6 Risk of Bias analysis\u003c/h2\u003e \u003cp\u003eThe Cochrane tool (RoB2) was used to assess the risk of bias, while publication bias was evaluated using Egger\u0026rsquo;s weighted regression test. If publication bias was detected, the trim-and-fill method was used to estimate its potential impact on the overall effect sizes.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e2.7 Data Synthesis and Statistical Analysis\u003c/h2\u003e \u003cp\u003eFor continuous outcomes (Pain score, inflammation and redness), we will compute mean differences, along with 95% confidence intervals (CIs). Given the anticipated considerable between-study heterogeneity, we will utilize a random-effects model with 95% confidence interval. The Sidik\u0026ndash;Jonkman estimator with Hartaung-Knapp (HK) adjustments will be employed to pool effect sizes.\u003c/p\u003e \u003cp\u003eBetween-study heterogeneity will be assessed using Cochran\u0026rsquo;s Q test, I square test, and prediction intervals. Meta-regression and subgroup analyses will be performed to investigate potential sources of heterogeneity. The meta- regression analysis will be carried out with a random-effects model. Furthermore, subgroup interactions will be tested with the chi-square test. Sensitivity analyses will be performed initially using the leave-one-out approach to assess the influence of individual trials on the overall effect estimate.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Study Characteristics\u003c/h2\u003e \u003cp\u003eA total of two randomized controlled trials (RCTs) met the inclusion criteria for this systematic review (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Both studies were conducted in Iran and evaluated the efficacy of curcumin-based nanoparticle formulations in the prevention or treatment of radiotherapy-induced oral mucositis (OM) in patients with head and neck cancers. A summary of individual study characteristics is provided in \u003cb\u003eTable\u0026nbsp;1 (Appendix II\u003c/b\u003e).\u003c/p\u003e \u003cp\u003eThe study by Delavarian et al. (2019) included 32 patients (19 males and 13 females), with a mean age of 62.18\u0026thinsp;\u0026plusmn;\u0026thinsp;15.07 years in the treatment group and 55.87\u0026thinsp;\u0026plusmn;\u0026thinsp;15.33 years in the control group [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The study employed a double-blind, placebo-controlled design, with participants receiving oral nano micellar curcumin (SinaCurcumin\u0026reg;) at a dose of 80 mg/day. The comparator was a placebo tablet containing lactose. The intervention began on the first day of radiotherapy and continued for six weeks, with assessments conducted on days 7, 14, 21, 28, 35, and 42 during which the mucositis was assessed [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The second study, by Ramezani et al. (2023), included 45 patients (23 males and 14 females) aged 53.36\u0026thinsp;\u0026plusmn;\u0026thinsp;15.99 years, all diagnosed with grades 1 to 3 Oral Mucositis [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Participants were randomized to receive either curcumin mouthwash (0.1% w/v), curcumin nano capsules (40 mg curcuminoids), or a placebo mouthwash over a three-week period, with weekly follow-ups [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The study was single-blinded, with patients unaware of the treatment received. Both studies utilized standard clinical mucositis grading systems: the WHO oral mucositis grading scale [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], with the National Rating Scale (NRS) additionally applied in the Ramezani et al. study [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Formulation and Dosage Comparison\u003c/h2\u003e \u003cp\u003eAlthough both trials used curcumin nanoparticles, they differed in how they were delivered. Delavarian et al. used a commercial nano micellar curcumin (SinaCurcumin\u0026reg;) taken orally at 80 mg/day throughout radiotherapy, aiming for consistent systemic absorption [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Ramezani et al., on the other hand, combined topical curcumin mouthwash with oral nano capsules, offering both local and systemic action [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Both approaches showed positive outcomes, suggesting that curcumin is effective in various nano formulations and delivery routes [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Efficacy in Reducing Oral Mucositis Severity\u003c/h2\u003e \u003cp\u003eBoth studies reported that curcumin nanoparticle-based interventions were effective in reducing the severity and progression of oral mucositis compared to placebo controls [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In Delavarian et al., oral administration of nano micellar curcumin led to lower mucositis grades at each evaluation point compared to placebo [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. By day 14, most patients in the treatment group maintained at Grade 0 or Grade 1, whereas the placebo group showed a steady progression to Grade 2 and Grade 3 mucositis by week 3 and beyond [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Specifically, none of the study group patients developed grade 1 mucositis after 1 week, while 37.5% of the control group did. After 2 weeks, only 25% of the study group developed grade 1, compared to 50% in the control group [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Although mucositis developed in both groups, the onset was delayed, and the severity was reduced in the curcumin group [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In Ramezani et al., both curcumin-treated groups (mouthwash and nano capsule) demonstrated a significant reduction in mucositis scores compared to placebo by week 3 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).(13) In weeks 1 and 2, no significant differences were observed among the three groups; however, the therapeutic effect became marked at the third week [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. This highlights the time-dependent efficacy of curcumin formulations in mucosal recovery.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Pain Relief and Symptom Management\u003c/h2\u003e \u003cp\u003ePain levels were assessed using the Visual Analog Scale (VAS) or Numerical Rating Scale (NRS). In Ramezani et al., although weeks 1 and 2 did not show significant intergroup differences, by week 3, the VAS scores in both curcumin-treated groups were significantly lower than the placebo group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), showing a notable symptom relief on prolonged usage of the medication [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Delavarian et al. did not report detailed VAS pain scores, and the study primarily focused on the prevention and reduction of OM severity, the observed improvements directly translate into significant pain relief and better symptom management for patients [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. By delaying onset, reducing severity, and improving food intake, nanomicelle curcumin helps alleviate the painful and debilitating effects of oral mucositis, thereby improving the patient's quality of life during critical cancer treatment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e3.5 Inflammation, Redness, and Tissue Healing\u003c/h2\u003e \u003cp\u003eBoth studies noted reduction in inflammation and erythema, although not quantified using biochemical markers. Delavarian et al. categorized mucositis severity based on presence of erythema, pseudomembrane formation, and ulceration. Participants receiving nanocurcumin maintained lower grades, with minimal or no progression to confluent pseudomembrane or necrosis[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The study group had a lower grade of mucositis compared to the control group throughout the treatment. For instance, grade 3 mucositis was observed in 50% of the control group after 3 weeks, while only 33.3% of the study group reached this grade after 4 weeks [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. At the end of the radiation therapy course, the NCI-CTC v.2 scores indicated that the study group had a mean score of 1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.84, while the control group had a mean score of 1.78\u0026thinsp;\u0026plusmn;\u0026thinsp;0.42. This difference was statistically significant (P\u0026thinsp;=\u0026thinsp;0.005) [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Ramezani et al. reported clinical resolution of inflammation and redness by the end of three weeks in the curcumin groups, with mucosal surfaces appearing near normal in most patients, while persistent erythema and ulceration were noted in the placebo group [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003e3.6 Safety and Tolerability\u003c/h2\u003e \u003cp\u003eNo serious adverse events were reported in either study. Participants tolerated both oral and topical curcumin formulations well, with no discontinuation due to side effects[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. This reinforces the safety profile of curcumin nanoparticles, making them suitable for extended use during chemoradiotherapy.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003e3.7 Follow-up and Clinical Impact\u003c/h2\u003e \u003cp\u003eThe follow-up period in Delavarian et al. extended across six weeks, aligning with the standard course of radiotherapy [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], while Ramezani et al. followed patients for three weeks post-intervention [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Both studies concluded that curcumin nanoparticles can effectively reduce severity, delay the onset, and accelerate the healing of oral mucositis, with potential for integration into routine oncology care[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003e3.8 Risk of Bias\u003c/h2\u003e \u003cp\u003eBoth studies [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] were of low risk, however Ramezani et al study have some concerns due to missing data (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis systematic review evaluated the effectiveness of curcumin nanoparticles in the prevention and management of oral mucositis in patients undergoing radiotherapy for head and neck cancers. The findings from the two included randomized controlled trials demonstrate that curcumin nanoparticles offer a promising therapeutic option having shown delayed onset of oral mucositis with significant reduction in severity and improved tissue healing compared to placebo [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. These results support the growing body of evidence which suggests that nano-formulated curcumin has enhanced clinical efficacy compared to traditional curcumin preparations, primarily due to improved bioavailability and targeted tissue delivery [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe results of this systematic review, encompassing two randomized controlled trials, provide compelling evidence that curcumin nanoparticle-based interventions are a safe and effective strategy for managing radiotherapy-induced oral mucositis. The findings consistently demonstrate a significant reduction in mucositis severity and pain, delayed onset, and improved tissue healing compared to placebo, confirming the therapeutic potential of this novel formulation [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA key strength of the reviewed studies is their focus on nanocurcumin, which addresses the critical issue of poor bioavailability that has historically limited the clinical application of standard curcumin [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The distinct delivery methods employed, oral nano micellar capsules in the study by Delavarian et al. and a combination of topical mouthwash and oral nano capsules in Ramezani et al., both yielded positive outcomes [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. This suggests that the enhanced absorption and targeted delivery provided by nanotechnological approaches are central to the observed efficacy. The fact that both systemic (oral capsules) and local (mouthwash) administrations were successful opens the door for a flexible, multi-modal approach to treatment, where systemic effects can target underlying inflammatory pathways while topical applications provide direct relief to mucosal surfaces [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAnother important observation is the consistently lower mucositis severity scores in the treatment groups. For example, Delavarian et al. noted that those receiving the nano micellar capsules had significantly milder mucositis grades throughout the six-week treatment window, and these differences were statistically meaningful by the end of the study [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Similarly, Ramezani et al. reported a clear improvement by the third week in the curcumin groups [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. These results imply that curcumin nanoparticles not only slow the onset of mucositis but may also promote quicker recovery once symptoms develop. The delayed onset of mucositis observed by Delavarian et al. is also a critical clinical benefit, as it implies that patients can maintain nutritional intake with reduced likelihood of treatment interruptions.\u003c/p\u003e \u003cp\u003e In the same vein, pain relief, which is a primary concern for patients with oral mucositis, was also significantly improved by the nanocurcumin interventions. Ramezani et al.'s findings that both curcumin groups had significantly lower VAS scores by week 3 highlight the clinical relevance of this treatment. While Delavarian et al. did not report detailed pain scores, the observed improvements in mucositis severity, which is directly correlated with pain, suggest a positive impact on patient comfort and quality of life. This is further supported by the noted improvements in symptoms like difficulty swallowing [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe safety and tolerability of curcumin nanoparticles, as highlighted by both studies, are major advantages [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].With no serious adverse events and no withdrawals due to side effects, nanocurcumin emerges as a well-tolerated option for a patient population already burdened by the side effects of cancer treatment. This excellent safety profile, coupled with its demonstrated efficacy, makes it a highly attractive candidate for integration into standard supportive care protocols.\u003c/p\u003e \u003cp\u003eHowever, despite these strengths, the review has several limitations. The evidence base is restricted to just two studies, both conducted in Iran. While the designs of the trials were rigorous, including a double-blind, placebo-controlled trial, their relatively small sample sizes and limited geographic scope may affect the applicability of the results to wider populations. Also, the lack of detailed reporting on pain scores in one of the studies also represents a gap in the available evidence. Finally, the differences in formulation like micellar capsules, mouthwash and nano capsules, and treatment duration across the studies, while highlighting the versatility of nanocurcumin, make direct comparisons and meta-analysis challenging.\u003c/p\u003e \u003cp\u003eFuture research should aim to address these limitations. Larger multi-centre international randomized controlled trials are needed to confirm these findings across diverse populations and cancer types. Studies should also standardize the reporting of outcomes, particularly pain scores, to allow for more robust statistical analysis. Additionally, head-to-head comparisons of different nanocurcumin formulations could provide valuable insights into optimal delivery methods. Finally, investigations into the precise molecular mechanisms of nanocurcumin in human subjects, beyond its established anti-inflammatory and antioxidant properties, would further strengthen the evidence base for its clinical use.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis systematic review provides consistent evidence that curcumin nanoparticle-based formulations are a safe and effective intervention for the prevention and management of oral mucositis. The benefits of CNPs include; delayed onset of mucositis, reduction in pain severity, mucosal healing, and improved patient comfort, with no reported serious adverse effects. Nevertheless, the limited number of available studies, small sample sizes, necessitate caution in generalizing results. Future studies should look toward designing large-scale, multi-center trials with standardized outcome measures and direct comparisons of various nanocurcumin delivery systems are warranted to establish optimal protocols and confirm the broader applicability of these promising findings.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cul\u003e\n \u003cli\u003eCNP: Curcumin NanoParticle\u003c/li\u003e\n \u003cli\u003ePRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses\u003c/li\u003e\n \u003cli\u003eROB: Risk Of Bias\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eNF-\u0026kappa;B: Nuclear Factor kappa-light\u003c/li\u003e\n \u003cli\u003eMeSH: Medical Subject Headings\u003c/li\u003e\n \u003cli\u003eOM: Oral Mucositis\u003c/li\u003e\n \u003cli\u003eGRADE:\u0026nbsp;Grading of Recommendations Assessment, Development, and Evaluation\u003c/li\u003e\n \u003cli\u003eVAS: Visual Assessment Scale\u003c/li\u003e\n \u003cli\u003eNRS: Numerical Rating Scale\u003c/li\u003e\n \u003cli\u003eCI: Confidence Interval\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u003c/strong\u003e None\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of conflicting interest:\u003c/strong\u003e The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding statement: \u003c/strong\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval and informed consent statements: \u003c/strong\u003eNot Applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement:\u003c/strong\u003e All data generated or analyzed during this study are included in this published article and its supplementary information files.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKarlsson C, Bohm N, Andersson JS, Finizia C, Almst\u0026aring;hl A (2024) Prospective study on health-related quality of life, oral mucositis and oral health on during treatment of head and neck cancer. BMC Oral Health 24(1):697. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/s12903-024-04466-5\u003c/span\u003e\u003cspan address=\"10.1186/s12903-024-04466-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePacheco R, Cavacas MA, Mascarenhas P, Oliveira P, Zagalo C Incidence of oral mucositis in patients undergoing head and neck cancer treatment: Systematic review and meta-analysis. InMedical Sciences Forum 2021 Jul 21 (Vol. 5, No. 1, p. 23). MDPI. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3390/msf2021005023\u003c/span\u003e\u003cspan address=\"10.3390/msf2021005023\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIovoli AJ, Turecki L, Qiu ML, Khan M, Smith K, Yu H, Ma SJ, Farrugia MK, Singh AK (2023) Severe oral mucositis after intensity-modulated radiation therapy for head and neck cancer. JAMA Netw open 6(10):e2337265. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1001/jamanetworkopen.2023.37265\u003c/span\u003e\u003cspan address=\"10.1001/jamanetworkopen.2023.37265\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePai RR, Ongole R, Banerjee S (2025) Retrospective evaluation of oral complications following radiotherapy and chemoradiation in patients with head and neck Cancer. Sci Rep 15(1):24726. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/s41598-025-10598-7\u003c/span\u003e\u003cspan address=\"10.1038/s41598-025-10598-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLalla RV, Bowen J, Barasch A, Elting L, Epstein J, Keefe DM, McGuire DB, Migliorati C, Nicolatou-Galitis O, Peterson DE, Raber‐Durlacher JE (2014) MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer 120(10):1453\u0026ndash;1461. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/cncr.28592\u003c/span\u003e\u003cspan address=\"10.1002/cncr.28592\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTagde P, Tagde P, Islam F, Tagde S, Shah M, Hussain ZD, Rahman MH, Najda A, Alanazi IS, Germoush MO, Mohamed HR (2021) The multifaceted role of curcumin in advanced nanocurcumin form in the treatment and management of chronic disorders. Molecules 26(23):7109. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3390/molecules26237109\u003c/span\u003e\u003cspan address=\"10.3390/molecules26237109\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAggarwal BB, Sundaram C, Malani N, Ichikawa H Curcumin: the Indian solid gold. The molecular targets and therapeutic uses of curcumin in health and disease. 2007 Jan 1:1\u0026ndash;75. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/978-0-387-46401-5_1\u003c/span\u003e\u003cspan address=\"10.1007/978-0-387-46401-5_1\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHewlings SJ, Kalman DS, Curcumin (2017) A review of its effects on human health. Foods 6(10):92. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3390/foods6100092\u003c/span\u003e\u003cspan address=\"10.3390/foods6100092\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLopresti AL (2018) The problem of curcumin and its bioavailability: could its gastrointestinal influence contribute to its overall health-enhancing effects? Adv Nutr 9(1):41\u0026ndash;50. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/advances/nmx011\u003c/span\u003e\u003cspan address=\"10.1093/advances/nmx011\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMohanty C, Das M, Sahoo SK (2012) Emerging role of nanocarriers to increase the solubility and bioavailability of curcumin. Expert Opin Drug Deliv 9(11):1347\u0026ndash;1364. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1517/17425247.2012.724676\u003c/span\u003e\u003cspan address=\"10.1517/17425247.2012.724676\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKia SJ, Basirat M, Saedi HS, Arab SA (2021) Effects of nanomicelle curcumin capsules on prevention and treatment of oral mucosits in patients under chemotherapy with or without head and neck radiotherapy: a randomized clinical trial. BMC Complement Med Ther 21(1):232. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/s12906-021-03400-4\u003c/span\u003e\u003cspan address=\"10.1186/s12906-021-03400-4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShah S, Rath H, Sharma G, Senapati SN, Mishra E (2020) Effectiveness of curcumin mouthwash on radiation-induced oral mucositis among head and neck cancer patients: A triple-blind, pilot randomised controlled trial. Indian J Dent Res 31(5):718\u0026ndash;727. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.4103/ijdr.ijdr_822_18\u003c/span\u003e\u003cspan address=\"10.4103/ijdr.ijdr_822_18\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRamezani V, Ghadirian S, Shabani M, Boroumand MA, Daneshvar R, Saghafi F (2023) Efficacy of curcumin for amelioration of radiotherapy-induced oral mucositis: a preliminary randomized controlled clinical trial. BMC Cancer 23(1):354. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/s12885-023-10730-8\u003c/span\u003e\u003cspan address=\"10.1186/s12885-023-10730-8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePage MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Akl EA, Brennan SE, Chou R (2021) The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e372.doi:https://doi.org/10.1136/bmj.n71\u003c/span\u003e\u003cspan address=\"372.doi:10.1136/bmj.n71\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOuzzani M, Hammady H, Fedorowicz Z, Elmagarmid A (2016) Rayyan\u0026mdash;a web and mobile app for systematic reviews. Syst reviews 5(1):210. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/s13643-016-0384-4\u003c/span\u003e\u003cspan address=\"10.1186/s13643-016-0384-4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDelavarian Z, Pakfetrat A, Ghazi A, Jaafari MR, Homaei Shandiz F, Dalirsani Z, Mohammadpour AH, Rahimi HR (2019) Oral administration of nanomicelle curcumin in the prevention of radiotherapy-induced mucositis in head and neck cancers. Spec Care Dentist 39(2):166\u0026ndash;172. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/scd.12358\u003c/span\u003e\u003cspan address=\"10.1111/scd.12358\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVilla A, Vollemans M, De Moraes A, Sonis S (2021) Concordance of the WHO, RTOG, and CTCAE v4. 0 grading scales for the evaluation of oral mucositis associated with chemoradiation therapy for the treatment of oral and oropharyngeal cancers. Support Care Cancer 29(10):6061\u0026ndash;6068. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00520-021-06177-x\u003c/span\u003e\u003cspan address=\"10.1007/s00520-021-06177-x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDharman S, Maragathavalli G, Shanmugasundaram K, Shanmugam RK (2021) A systematic review and meta-analysis on the efficacy of curcumin/turmeric for the prevention and amelioration of radiotherapy/radiochemotherapy induced oral mucositis in head and neck cancer patients. Asian Pac J cancer prevention: APJCP 22(6):1671. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.31557/APJCP.2021.22.6.1671\u003c/span\u003e\u003cspan address=\"10.31557/APJCP.2021.22.6.1671\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTabanelli R, Brogi S, Calderone V (2021) Improving curcumin bioavailability: Current strategies and future perspectives. Pharmaceutics 13(10):1715. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/pharmaceutics13101715\u003c/span\u003e\u003cspan address=\"10.3390/pharmaceutics13101715\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBoroughani M, Moaveni AK, Hatami P, Mansoob Abasi N, Seyedoshohadaei SA, Pooladi A, Moradi Y, Rahimi Darehbagh R (2024) Nanocurcumin in cancer treatment: a comprehensive systematic review. Discover Oncol 15(1):515. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s12672-024-01272-x\u003c/span\u003e\u003cspan address=\"10.1007/s12672-024-01272-x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Department of Oral and Maxillofacial Pathology, Saveetha Dental College and Hospitals,India","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Curcumin nanoparticles, oral mucositis, radiotherapy, nanotechnology, pain relief, mouth ulcers","lastPublishedDoi":"10.21203/rs.3.rs-8470615/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8470615/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eOral mucositis is a painful oral condition with diverse etiology and limited effective treatment modalities. Curcumin, a natural compound from curcumin longa, has anti-inflammatory and healing properties but is poorly absorbed by the body. A few studies have reported how curcumin nanoparticles (CNPs) have been created to solve this problem and improve effectiveness. This study reviewed how well CNPs work in treating oral mucositis.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003e We followed PRISMA guidelines and searched major databases for clinical studies using curcumin nanoparticles to treat oral mucositis. Only human studies comparing CNPs to placebos or standard treatments were included. Two reviewers independently selected and analyzed studies. The risk of bias and quality of the studies were assessed using Cochrane\u0026rsquo;s Risk of Bias tool 2 for randomized controlled trials.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eTwo clinical trials from Iran were included. One trial used nano-curcumin capsules, and the other trial combined capsules with mouthwash. However, both studies showed that CNPs reduced the severity of mucositis, delayed its onset, and assist in mucosal healing. Patients using CNPs had less pain and fewer ulcers by the third week. In additon, CNPs did not had any serious side effects.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eCNPs was found a safe and effective option for reducing the severity and pain of oral mucositis. Although the findings are promising, more studies in different countries are needed to confirm these results.\u003c/p\u003e","manuscriptTitle":"Effectiveness of Curcumin Nanoparticles in the Management of Oral Mucositis: A Systematic Review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-06 11:52:05","doi":"10.21203/rs.3.rs-8470615/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f6c4ffeb-3941-44cf-a231-0dd6fd9c7133","owner":[],"postedDate":"January 6th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":60313879,"name":"Dentistry"},{"id":60313880,"name":"Oncology"}],"tags":[],"updatedAt":"2026-01-06T11:52:05+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-06 11:52:05","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8470615","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8470615","identity":"rs-8470615","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}