{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T15:03:23Z","timestamp":1791385403155,"version":"4.3.3"},"reference-count":104,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T00:00:00Z","timestamp":1750291200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"JSPS KAKENHI","doi-asserted-by":"publisher","award":["25K20281"],"award-info":[{"award-number":["25K20281"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"name":"TERUMO LIFE SCIENCE FOUNDATION, Kanagawa, Japan","award":["25K20281"],"award-info":[{"award-number":["25K20281"]}]},{"name":"Takeda Science Foundation, Osaka, Japan","award":["25K20281"],"award-info":[{"award-number":["25K20281"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Periodontitis is a highly prevalent, irreversible inflammatory disease characterized by the destruction of tooth-supporting tissues, eventually leading to tooth loss. Conventional treatment involves the mechanical removal of the subgingival biofilm, which is a major cause of gingival inflammation. However, the inaccessibility of deep-seated polymicrobial biofilms limits its effectiveness. Despite the adjunct use of systemic antimicrobials, their low site-specific bioavailability and systemic side effects remain concerns. Local drug administration offers a targeted alternative. However, the dynamic oral environment, which is characterized by continuous salivary and gingival crevicular fluid flow, poses challenges in maintaining therapeutic drug levels. Drug delivery systems (DDSs) provide technical solutions to overcome these limitations. With advancements in materials science and nanotechnology, diverse local DDS (LDDS) formulations tailored for periodontal applications have been developed. While traditionally focused on infection control, the application of LDDSs has expanded beyond antimicrobial therapy. Increasing attention has been paid to LDDS-based regenerative strategies, which aim to overcome the limitations of conventional regenerative therapies. This review aims to provide a comprehensive overview of the current and emerging DDS strategies in periodontal therapy, focusing on their applications in infection management and bone regeneration and discussing their limitations and prospects for clinical translation.<\/jats:p>","DOI":"10.3390\/biom15060903","type":"journal-article","created":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T09:57:48Z","timestamp":1750327068000},"page":"903","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Advances in Local Drug Delivery for Periodontal Treatment: Present Strategies and Future Directions"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2875-2111","authenticated-orcid":false,"given":"Mayuka","family":"Nakajima","sequence":"first","affiliation":[{"name":"Division of Periodontology, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayuko","family":"Yanagawa","sequence":"additional","affiliation":[{"name":"Division of Periodontology, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Honoka","family":"Takikawa","sequence":"additional","affiliation":[{"name":"Division of Periodontology, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-1599-1208","authenticated-orcid":false,"given":"Truong Tran","family":"Thien","sequence":"additional","affiliation":[{"name":"Division of Periodontology, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorena","family":"Zegarra-Caceres","sequence":"additional","affiliation":[{"name":"Division of Periodontology, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0524-2781","authenticated-orcid":false,"given":"Chunyang","family":"Yan","sequence":"additional","affiliation":[{"name":"Division of Periodontology, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7019-1872","authenticated-orcid":false,"given":"Koichi","family":"Tabeta","sequence":"additional","affiliation":[{"name":"Division of Periodontology, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1111\/jre.12436","article-title":"Impact of periodontal disease on quality of life: A systematic review","volume":"52","author":"Ferreira","year":"2017","journal-title":"J. Periodontal Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1111\/j.1600-051X.2007.01133.x","article-title":"Severe periodontitis is associated with systemic inflammation and a dysmetabolic status: A case-control study","volume":"34","author":"Nibali","year":"2007","journal-title":"J. Clin. Periodontol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1128\/CMR.13.4.547","article-title":"Systemic diseases caused by oral infection","volume":"13","author":"Li","year":"2000","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1177\/0022034517693566","article-title":"Global, regional, and national prevalence, incidence, and disability-adjusted life years for oral conditions for 195 countries, 1990\u20132015: A systematic analysis for the Global Burden of diseases, injuries, and risk factors","volume":"96","author":"Kassebaum","year":"2017","journal-title":"J Dent. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"S23","DOI":"10.1111\/jcpe.12671","article-title":"Role of microbial communities in the pathogenesis of periodontal diseases and caries","volume":"44","author":"Mira","year":"2017","journal-title":"J. Clin. Periodontol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Velsko, I.M., and Shaddox, L.M. (2018). Consistent and reproducible long-term in vitro growth of health and disease-associated oral subgingival biofilms. BMC Microbiol., 18.","DOI":"10.1186\/s12866-018-1212-x"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Polizzi, A., Donzella, M., Nicolosi, G., Santonocito, S., Pesce, P., and Isola, G. (2022). Drugs for the Quorum Sensing Inhibition of Oral Biofilm: New Frontiers and Insights in the Treatment of Periodontitis. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14122740"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1034\/j.1601-0825.9.s1.7.x","article-title":"Systemic antimicrobials in the treatment of chronic periodontal diseases: A dilemma","volume":"9","author":"Addy","year":"2003","journal-title":"Oral Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.12688\/f1000research.140173.1","article-title":"Oleogel-based drug delivery for the treatment of periodontitis: Current strategies and future perspectives","volume":"12","author":"Karmakar","year":"2023","journal-title":"F1000Research"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"363","DOI":"10.3109\/10717544.2014.935531","article-title":"Advanced drug delivery approaches against periodontitis","volume":"23","author":"Joshi","year":"2016","journal-title":"Drug Deliv."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1177\/0022034515618887","article-title":"Regenerative medicine for periodontal and Peri-implant diseases","volume":"95","author":"Larsson","year":"2016","journal-title":"J. Dent. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"6857","DOI":"10.2147\/IJN.S465089","article-title":"Nanoparticles in periodontitis therapy: A review of the current situation","volume":"19","author":"Wang","year":"2024","journal-title":"Int. J. Nanomed."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1902\/jop.1993.64.8s.782","article-title":"Controlled-release local delivery antimicrobials in periodontics: Prospects for the future","volume":"64","author":"Kornman","year":"1993","journal-title":"J. Periodontol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.jconrel.2021.03.041","article-title":"Local drug delivery systems as therapeutic strategies against periodontitis: A systematic review","volume":"333","author":"Wei","year":"2021","journal-title":"J. Control. Release"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1016\/j.drudis.2008.07.010","article-title":"Recent approaches for the treatment of periodontitis","volume":"13","author":"Jain","year":"2008","journal-title":"Drug Discov. Today"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.jconrel.2017.03.016","article-title":"Electrospun starch nanofibers: Recent advances, challenges, and strategies for potential pharmaceutical applications","volume":"252","author":"Liu","year":"2017","journal-title":"J. Control. Release"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"8241","DOI":"10.1021\/am402376c","article-title":"Triaxial electrospun nanofiber membranes for controlled dual release of functional molecules","volume":"5","author":"Han","year":"2013","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1111\/j.1600-0765.1996.tb00518.x","article-title":"Use of the polymeric matrix as internal standard for quantitation of in vivo delivery of tetracycline HCl from Actisite tetracycline fiber during periodontal treatment","volume":"31","author":"Litch","year":"1996","journal-title":"J. Periodontal Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1111\/j.1600-051X.1979.tb02186.x","article-title":"Periodontal therapy by local delivery of tetracycline","volume":"6","author":"Goodson","year":"1979","journal-title":"J. Clin. Periodontol"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1039\/C6BM00646A","article-title":"Electrospun poly(lactic acid) fibers containing novel chlorhexidine particles with sustained antibacterial activity","volume":"5","author":"Luo","year":"2016","journal-title":"Biomater. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.dental.2011.12.006","article-title":"Release of metronidazole from electrospun poly(L-lactide-co-D\/L-lactide) fibers for local periodontitis treatment","volume":"28","author":"Reise","year":"2012","journal-title":"Dent. Mater."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"130","DOI":"10.4103\/0972-124X.84381","article-title":"Evaluation of commercially available biodegradable tetracycline fiber therapy in chronic periodontitis","volume":"15","author":"Sachdeva","year":"2011","journal-title":"J. Indian Soc. Periodontol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2990","DOI":"10.1002\/aic.690491202","article-title":"Advances in biomaterials, drug delivery, and bionanotechnology","volume":"49","author":"Langer","year":"2003","journal-title":"AIChE J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1902\/jop.1990.61.1.30","article-title":"In vitro release of doxycycline from bioabsorbable materials and acrylic strips","volume":"61","author":"Larsen","year":"1990","journal-title":"J. Periodontol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1902\/jop.1990.61.7.393","article-title":"A new degradable controlled release device for treatment of periodontal disease: In vitro release study","volume":"61","author":"Steinberg","year":"1990","journal-title":"J. Periodontol."},{"key":"ref_26","first-page":"E75","article-title":"Micromatricial metronidazole benzoate film as a local mucoadhesive delivery system for treatment of periodontal diseases","volume":"8","author":"Ashri","year":"2007","journal-title":"AAPS PharmSciTech"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/S0939-6411(00)00086-2","article-title":"Local delivery of antimicrobial agents for the treatment of periodontal diseases","volume":"50","author":"Gurny","year":"2000","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1902\/jop.2008.070308","article-title":"Clinical and microbiologic effects of subgingival controlled-release delivery of chlorhexidine chip in the treatment of periodontitis: A multicenter study","volume":"79","author":"Paolantonio","year":"2008","journal-title":"J. Periodontol"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2197","DOI":"10.1002\/jbm.b.32788","article-title":"Formulation and evaluation of in situ forming PLA implant containing tinidazole for the treatment of periodontitis","volume":"100","author":"Qin","year":"2012","journal-title":"J. Biomed. Mater. Res. B Appl. Biomater."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1034\/j.1600-051x.2000.027012910.x","article-title":"Comparison of clinical outcomes following treatment of chronic adult periodontitis with subgingival scaling or subgingival scaling plus metronidazole gel","volume":"27","author":"Griffiths","year":"2000","journal-title":"J. Clin. Periodontol"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4155\/tde.15.83","article-title":"Oleogels: A promising tool for delivery of hydrophobic bioactive molecules","volume":"7","year":"2016","journal-title":"Ther. Deliv."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.1902\/jop.2009.090050","article-title":"Clinical, microbiologic, and biochemical effects of subgingival administration of a Xanthan-based chlorhexidine gel in the treatment of periodontitis: A randomized multicenter trial","volume":"80","author":"Paolantonio","year":"2009","journal-title":"J. Periodontol"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"439","DOI":"10.4103\/0972-124X.118313","article-title":"Efficacy of xanthan based chlorhexidine gel as an adjunct to scaling and root planing in treatment of the chronic periodontitis","volume":"17","author":"Jain","year":"2013","journal-title":"J. Indian Soc. Periodontol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Rebaka, V.P., Rachamalla, A.K., Batra, S., and Subbiah, N. (2020). State of the art and new perspectives in oleogels and applications. Sustainable Green Chemical Processes and their Allied Applications, Nanotechnology in the Life Sciences; Springer International Publishing.","DOI":"10.1007\/978-3-030-42284-4_6"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Vlachopoulos, A., Karlioti, G., Balla, E., Daniilidis, V., Kalamas, T., Stefanidou, M., Bikiaris, N.D., Christodoulou, E., Koumentakou, I., and Karavas, E. (2022). Poly(lactic acid)-based microparticles for drug delivery applications: An overview of recent advances. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14020359"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/j.jconrel.2015.09.001","article-title":"Polymeric nanoparticles and microparticles for the delivery of peptides, biologics, and soluble therapeutics","volume":"219","author":"Pagels","year":"2015","journal-title":"J. Control. Release"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.ijpharm.2015.10.057","article-title":"Double emulsion solvent evaporation techniques used for drug encapsulation","volume":"496","author":"Iqbal","year":"2015","journal-title":"Int. J. Pharm."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1111\/j.1600-0501.2006.01269.x","article-title":"Antimicrobial therapy using a local drug delivery system (Arestin) in the treatment of peri-implantitis. I: Microbiological outcomes","volume":"17","author":"Persson","year":"2006","journal-title":"Clin. Oral Implants Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"79","DOI":"10.4103\/0972-124X.55844","article-title":"Effect of a controlled release device containing minocycline microspheres on the treatment of chronic periodontitis: A comparative study","volume":"13","author":"Gopinath","year":"2009","journal-title":"J. Indian Soc. Periodontol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1034\/j.1600-051X.2003.00375.x","article-title":"Locally delivered minocycline microspheres for the treatment of periodontitis in smokers: Efficacy of minocycline microspheres in smokers","volume":"30","author":"Paquette","year":"2003","journal-title":"J. Clin. Periodontol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.jddst.2019.04.031","article-title":"Influence of formulation parameters on encapsulation of doxycycline in PLGA microspheres prepared by double emulsion technique for the treatment of periodontitis","volume":"52","author":"Ali","year":"2019","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1111\/prd.12297","article-title":"The role of inflammation and genetics in periodontal disease","volume":"83","author":"Loos","year":"2020","journal-title":"Periodontol. 2000"},{"key":"ref_43","first-page":"123","article-title":"Systemic Chemotherapeutic Agents as Adjunctive Periodontal Therapy: A Narrative Review and Suggested Clinical Recommendations","volume":"17","author":"Sheridan","year":"2015","journal-title":"J. Int. Acad. Periodontol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1128\/microbiolspec.MB-0010-2014","article-title":"Antimicrobial Tolerance in Biofilms","volume":"3","author":"Stewart","year":"2015","journal-title":"Microbiol. Spectr."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1111\/idj.12146","article-title":"Antibiotics in dental practice: How justified are we","volume":"65","author":"Oberoi","year":"2015","journal-title":"Int. Dent. J."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Wang, Y., Li, J., Tang, M., Peng, C., Wang, G., Wang, J., Wang, X., Chang, X., Guo, J., and Gui, S. (2023). Smart stimuli-responsive hydrogels for drug delivery in periodontitis treatment. Biomed. Pharmacother., 162.","DOI":"10.1016\/j.biopha.2023.114688"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1902\/jop.2016.160189","article-title":"Inhibition of periodontitis induction using a stimuli-responsive hydrogel carrying naringin","volume":"88","author":"Chang","year":"2017","journal-title":"J. Periodontol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"11903","DOI":"10.1039\/D3RA00904A","article-title":"Injectable adhesive carboxymethyl chitosan-based hydrogels with self-mending and antimicrobial features for the potential management of periodontal diseases","volume":"13","author":"Lin","year":"2023","journal-title":"RSC Adv."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"525","DOI":"10.3109\/10717544.2014.929195","article-title":"Preparation and characteristics of thermoresponsive gel of minocycline hydrochloride and evaluation of its effect on experimental periodontitis models","volume":"23","author":"Ruan","year":"2016","journal-title":"Drug Deliv."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1290","DOI":"10.1902\/jop.2012.120425","article-title":"Thermo-reversible green tea catechin gel for local application in chronic periodontitis: A 4-week clinical trial","volume":"84","author":"Chava","year":"2013","journal-title":"J. Periodontol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1080\/10717544.2016.1233591","article-title":"Formulation, in-vitro characterization and clinical evaluation of curcumin in-situ gel for treatment of periodontitis","volume":"24","author":"Nasra","year":"2017","journal-title":"Drug Deliv."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"e2403786","DOI":"10.1002\/advs.202403786","article-title":"A microenvironment-responsive, controlled release hydrogel delivering Embelin to promote bone repair of periodontitis via anti-infection and osteo-immune modulation","volume":"11","author":"Cai","year":"2024","journal-title":"Adv. Sci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3354","DOI":"10.1021\/acsami.9b17335","article-title":"Light-activable on-demand release of nano-antibiotic platforms for precise synergy of thermochemotherapy on periodontitis","volume":"12","author":"Zhang","year":"2020","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.1007\/s10856-009-3729-x","article-title":"Injectable thermosensitive hydrogel based on chitosan and quaternized chitosan and the biomedical properties","volume":"20","author":"Ji","year":"2009","journal-title":"J. Mater. Sci. Mater. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"5377","DOI":"10.2147\/IJN.S248538","article-title":"Hybrid Hydrogels for Synergistic Periodontal Antibacterial Treatment with Sustained Drug Release and NIR-Responsive Photothermal Effect","volume":"15","author":"Lin","year":"2020","journal-title":"Int. J. Nanomed."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Zheng, X., Dong, Z., Liang, Z., Liu, Y., Yin, X., Han, M., Cui, Z., Mei, X., and Gao, X. (2023). Photothermally responsive icariin and carbon nanofiber modified hydrogels for the treatment of periodontitis. Front. Bioeng. Biotechnol., 11.","DOI":"10.3389\/fbioe.2023.1207011"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Zhao, X., Yang, Y., Yu, J., Ding, R., Pei, D., Zhang, Y., He, G., Cheng, Y., and Li, A. (2022). Injectable hydrogels with high drug loading through B-N coordination and ROS-triggered drug release for efficient treatment of chronic periodontitis in diabetic rats. Biomaterials, 282.","DOI":"10.1016\/j.biomaterials.2022.121387"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Luo, Q., Yang, Y., Ho, C., Li, Z., Chiu, W., Li, A., Dai, Y., Li, W., and Zhang, X. (2024). Dynamic hydrogel-metal-organic framework system promotes bone regeneration in periodontitis through controlled drug delivery. J. Nanobiotechnol., 22.","DOI":"10.1186\/s12951-024-02555-9"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1177\/0022034519831931","article-title":"MMP-8-responsive polyethylene glycol hydrogel for intraoral drug delivery","volume":"98","author":"Guo","year":"2019","journal-title":"J. Dent. Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1111\/j.1600-0757.2005.00143.x","article-title":"Nanotechnology and its role in the management of periodontal diseases","volume":"40","author":"Kong","year":"2006","journal-title":"Periodontol. 2000"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1111\/prd.12341","article-title":"Sustained-release delivery of antimicrobial drugs for the treatment of periodontal diseases: Fantasy or already reality?","volume":"84","author":"Steinberg","year":"2020","journal-title":"Periodontol. 2000"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"103455","DOI":"10.1016\/j.drudis.2022.103455","article-title":"Engineered organic nanoparticles to combat biofilms","volume":"28","author":"Sheng","year":"2023","journal-title":"Drug Discov. Today"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.jconrel.2016.01.008","article-title":"Current applications of nanoparticles in infectious diseases","volume":"224","author":"Zazo","year":"2016","journal-title":"J. Control. Release"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2555","DOI":"10.2147\/IJN.S246764","article-title":"The antibacterial mechanism of silver nanoparticles and its application in dentistry","volume":"15","author":"Yin","year":"2020","journal-title":"Int. J. Nanomed."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"114636","DOI":"10.1016\/j.ecoenv.2023.114636","article-title":"Synthesis, applications, toxicity and toxicity mechanisms of silver nanoparticles: A review","volume":"253","author":"Nie","year":"2023","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"107004","DOI":"10.1016\/j.micpath.2024.107004","article-title":"Optimizing Desmostachya bipinnata-derived platinum nanoparticles for enhanced antibacterial and biofilm reduction","volume":"196","author":"Krishnasamy","year":"2024","journal-title":"Microb. Pathog."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"6772","DOI":"10.1021\/acs.nanolett.9b01716","article-title":"Yolk-shell structured Au nanostar@metal-organic framework for synergistic chemo-photothermal therapy in the second near-infrared window","volume":"19","author":"Deng","year":"2019","journal-title":"Nano Lett."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"111487","DOI":"10.1016\/j.matdes.2022.111487","article-title":"NIR-triggered tea polyphenol-modified gold nanoparticles-loaded hydrogel treats periodontitis by inhibiting bacteria and inducing bone regeneration","volume":"225","author":"Dong","year":"2023","journal-title":"Mater. Des."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"122802","DOI":"10.1016\/j.ijpharm.2023.122802","article-title":"A multiple controlled-release hydrophilicity minocycline hydrochloride delivery system for the efficient treatment of periodontitis","volume":"636","author":"Zhao","year":"2023","journal-title":"Int. J. Pharm."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"3217","DOI":"10.1007\/s00784-020-03652-3","article-title":"Local application of curcumin-loaded nanoparticles as an adjunct to scaling and root planing in periodontitis: Randomized, placebo-controlled, double-blind split-mouth clinical trial","volume":"25","author":"Fernandes","year":"2021","journal-title":"Clin. Oral Investig."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.jconrel.2019.01.036","article-title":"Functional assessment of peptide-modified PLGA nanoparticles against oral biofilms in a murine model of periodontitis","volume":"297","author":"Mahmoud","year":"2019","journal-title":"J. Control. Release"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Mahmoud, M.Y., Demuth, D.R., and Steinbach-Rankins, J.M. (2018). BAR-encapsulated nanoparticles for the inhibition and disruption of Porphyromonas gingivalis-Streptococcus gordonii biofilms. J Nanobiotechnol., 16.","DOI":"10.1186\/s12951-018-0396-4"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"36653","DOI":"10.1021\/acsomega.2c04723","article-title":"Isocorrole-loaded polymer nanoparticles for photothermal therapy under 980 nm light excitation","volume":"7","author":"Marek","year":"2022","journal-title":"ACS Omega"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"de Freitas, L.M., Calixto, G.M.F., Chorilli, M., Giusti, J.S.M., Bagnato, V.S., Soukos, N.S., Amiji, M.M., and Fontana, C.R. (2016). Polymeric nanoparticle-based photodynamic therapy for chronic periodontitis in vivo. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17050769"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.reactfunctpolym.2016.01.011","article-title":"Mucoadhesion: A promising approach in drug delivery system","volume":"100","author":"Mansuri","year":"2016","journal-title":"React. Funct. Polym."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1016\/j.ijbiomac.2020.06.211","article-title":"Chitosan biomaterials application in dentistry","volume":"162","author":"Fakhri","year":"2020","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"116163","DOI":"10.1016\/j.carbpol.2020.116163","article-title":"The effect of doxycycline-containing chitosan\/carboxymethyl chitosan nanoparticles on NLRP3 inflammasome in periodontal disease","volume":"237","author":"Xu","year":"2020","journal-title":"Carbohydr. Polym."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Lu, B., Lv, X., and Le, Y. (2019). Chitosan-modified PLGA nanoparticles for control-released drug delivery. Polymers, 11.","DOI":"10.3390\/polym11020304"},{"key":"ref_79","first-page":"592","article-title":"Minocycline hydrochloride liposome controlled-release gel improves rat experimental periodontitis","volume":"31","author":"Liu","year":"2013","journal-title":"Hua Xi Kou Qiang Yi Xue Za Zhi"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1016\/j.ijbiomac.2018.09.057","article-title":"A novel pH-responsive quaternary ammonium chitosan-liposome nanoparticles for periodontal treatment","volume":"129","author":"Hu","year":"2019","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.ijpharm.2017.06.037","article-title":"Tocosome: Novel drug delivery system containing phospholipids and tocopheryl phosphates","volume":"528","author":"Mozafari","year":"2017","journal-title":"Int. J. Pharm."},{"key":"ref_82","first-page":"26","article-title":"Main distinctions between tocosome and nano-liposome as drug delivery systems: A scientific and technical point of view","volume":"2","author":"Mozafari","year":"2023","journal-title":"Micro Nano Bio Asp."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1644","DOI":"10.1080\/09205063.2022.2068948","article-title":"Glucose-sensitive delivery of tannic acid by a photo-crosslinked chitosan hydrogel film for antibacterial and anti-inflammatory therapy","volume":"33","author":"Liu","year":"2022","journal-title":"J. Biomater. Sci. Polym. Ed."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"43441","DOI":"10.1021\/acsami.3c08336","article-title":"A novel injectable piezoelectric hydrogel for periodontal disease treatment","volume":"15","author":"Roldan","year":"2023","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Ma, S., Lu, X., Yu, X., Du, Y., Xu, S., Li, M., Peng, C., Liu, Z., and Deng, J. (2022). An injectable multifunctional thermo-sensitive chitosan-based hydrogel for periodontitis therapy. Biomater. Adv., 142.","DOI":"10.1016\/j.bioadv.2022.213158"},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Conte, R., Valentino, A., De Luca, I., Soares Pontes, G., Calarco, A., and Cerruti, P. (2024). Thermo-responsive hydrogel containing microfluidic chitosan nanoparticles loaded with Opuntia ficus-indica extract for periodontitis treatment. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25179374"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1080\/10717544.2019.1571121","article-title":"Hydrogel containing minocycline and zinc oxide-loaded serum albumin nanopartical for periodontitis application: Preparation, characterization and evaluation","volume":"26","author":"Mou","year":"2019","journal-title":"Drug Deliv."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"8113","DOI":"10.2147\/IJN.S434579","article-title":"Ebselen optimized the therapeutic effects of silver nanoparticles for periodontal treatment","volume":"18","author":"Liang","year":"2023","journal-title":"Int. J. Nanomed."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"6955","DOI":"10.1039\/C9TB01743G","article-title":"Novel nanoparticles of cerium-doped zeolitic imidazolate frameworks with dual benefits of antibacterial and anti-inflammatory functions against periodontitis","volume":"7","author":"Li","year":"2019","journal-title":"J. Mater. Chem. B Mater. Biol. Med."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"36077","DOI":"10.1021\/acsami.4c05722","article-title":"ZIF-8-based nanoparticles for inflammation treatment and oxidative stress reduction in periodontitis","volume":"16","author":"Li","year":"2024","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1002\/lsm.21069","article-title":"Photodynamic effects of methylene blue-loaded polymeric nanoparticles on dental plaque bacteria","volume":"43","author":"Patel","year":"2011","journal-title":"Lasers Surg. Med."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"445","DOI":"10.17219\/dmp\/150728","article-title":"Antibacterial and anti-inflammatory effects of a novel herb-mediated nanocomposite mouthwash in plaque-induced gingivitis: A randomized controlled trial","volume":"60","author":"Soundarajan","year":"2023","journal-title":"Dent. Med. Probl."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1007\/s00784-019-03005-9","article-title":"Novel 20% doxycycline-loaded PLGA nanospheres as adjunctive therapy in chronic periodontitis in type-2 diabetics: Randomized clinical, immune and microbiological trial","volume":"24","author":"Lecio","year":"2020","journal-title":"Clin. Oral Investig."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1002\/JPER.23-0328","article-title":"Suppression of subgingival bacteria by antimicrobial photodynamic therapy using transgingival irradiation: A randomized clinical trial","volume":"95","author":"Hayashi","year":"2024","journal-title":"J. Periodontol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.jconrel.2019.08.029","article-title":"Mechanistic study of transdermal delivery of macromolecules assisted by ionic liquids","volume":"311\u2013312","author":"Qi","year":"2019","journal-title":"J. Control. Release"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"e2004819","DOI":"10.1002\/advs.202004819","article-title":"Recent Advances in Ionic Liquids in Biomedicine","volume":"8","author":"Curreri","year":"2021","journal-title":"Adv. Sci."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.jconrel.2018.07.029","article-title":"Transdermal insulin delivery using choline-based ionic liquids (CAGE)","volume":"286","author":"Tanner","year":"2018","journal-title":"J. Control. Release"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"124544","DOI":"10.1016\/j.ijpharm.2024.124544","article-title":"Choline and geranate ionic liquid for subgingival biofilm control","volume":"662","author":"Yan","year":"2024","journal-title":"Int. J. Pharm."},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Nakajima, M., Tanner, E.E.L., Nakajima, N., Ibsen, K.N., and Mitragotri, S. (2021). Topical treatment of periodontitis using an iongel. Biomaterials, 276.","DOI":"10.1016\/j.biomaterials.2021.121069"},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Funda, G., Taschieri, S., Bruno, G.A., Grecchi, E., Paolo, S., Girolamo, D., and Del Fabbro, M. (2020). Nanotechnology scaffolds for alveolar bone regeneration. Materials, 13.","DOI":"10.3390\/ma13010201"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"eaay1240","DOI":"10.1126\/sciadv.aay1240","article-title":"Heparin-mediated delivery of bone morphogenetic protein-2 improves spatial localization of bone regeneration","volume":"6","author":"Hettiaratchi","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"5616","DOI":"10.1021\/acsnano.9b00788","article-title":"Sustained release of two bioactive factors from supramolecular hydrogel promotes periodontal bone regeneration","volume":"13","author":"Tan","year":"2019","journal-title":"ACS Nano"},{"key":"ref_103","first-page":"285","article-title":"Controlled-release of tetracycline and lovastatin by poly(D,L-lactide-co-glycolide acid)-chitosan nanoparticles enhances periodontal regeneration in dogs","volume":"11","author":"Lee","year":"2016","journal-title":"Int. J. Nanomed."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Ghavimi, M.A., Bani Shahabadi, A., Jarolmasjed, S., Memar, M.Y., Maleki Dizaj, S., and Sharifi, S. (2020). Nanofibrous asymmetric collagen\/curcumin membrane containing aspirin-loaded PLGA nanoparticles for guided bone regeneration. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-75454-2"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/6\/903\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:55:01Z","timestamp":1760032501000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/6\/903"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,19]]},"references-count":104,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["biom15060903"],"URL":"https:\/\/doi.org\/10.3390\/biom15060903","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,19]]}}}