Lulu Yang, Liang Shao, Puhua Hao, Jiaqi Song, Caiting Meng, Bin Zhu, Hongwen Yu, Wanglin Duan, Xiaohua Fang, Guanying Li, Shichang Liu
{"title":"萘普生共轭肽自组装水凝胶治疗骨关节炎。","authors":"Lulu Yang, Liang Shao, Puhua Hao, Jiaqi Song, Caiting Meng, Bin Zhu, Hongwen Yu, Wanglin Duan, Xiaohua Fang, Guanying Li, Shichang Liu","doi":"10.7150/thno.114781","DOIUrl":null,"url":null,"abstract":"<p><p><b>Rationale</b>: Osteoarthritis (OA), a highly prevalent chronic degenerative joint disease, lacks truly effective therapies. Current approaches are limited by systemic toxicity, short drug half-lives, and insufficient efficacy. To address this, we developed an innovative therapeutic approach integrating the pharmacological benefits of nonsteroidal anti-inflammatory drugs (NSAIDs) with the mechanical support and localized delivery advantages of hydrogels. <b>Methods</b>: Various naproxen-peptide conjugates are designed and synthesized. These candidates were screened based on self-assembly behavior, biocompatibility and cyclooxygenase-2 (COX-2) inhibition. NpxFFK underwent further studies including assessment of anti-inflammatory activities and mechanism of action <i>in vitro</i>. <i>In vivo</i> therapeutic efficacy was evaluated in OA rat model using footprinting assay, micro-CT imaging, MRI imaging, histological staining, and immunohistochemistry. The therapeutic mechanism is explored via RNA sequencing. <b>Results</b>: Among naproxen-peptide conjugates NpxFFX (X = R, H, K, E) tested, NpxFFK demonstrated superior anti-inflammatory efficacy. It self-assembled into a stable hydrogel, exhibiting enhanced retention within the joint cavity and providing sustained anti-inflammatory action. <i>In vitro</i> studies revealed that NpxFFK effectively inhibited COX-2 activity, consequently suppressing key inflammatory factors (IL-1β, IL-6, IL-1, and TNF-α). Furthermore, it reprogramed macrophage polarization from M1 toward M2 and promoted chondrocyte proliferation. <i>In vivo</i> experiments demonstrate the NpxFFK hydrogel significantly mitigated articular degradation in OA rats, outperforming clinical treatments (naproxen treatment or hyaluronic acid treatment), thereby validating its therapeutic potential for OA. <b>Conclusions</b>: By integrating NSAID pharmacology with self-assembling peptide hydrogel delivery platform, we present a multifunctional strategy that significantly improves upon current OA treatments, underscoring its promise for translational healthcare innovation in OA management.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 17","pages":"8779-8794"},"PeriodicalIF":13.3000,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439141/pdf/","citationCount":"0","resultStr":"{\"title\":\"Self-Assembling Hydrogels of Naproxen-Conjugated Peptides for Osteoarthritis Treatment.\",\"authors\":\"Lulu Yang, Liang Shao, Puhua Hao, Jiaqi Song, Caiting Meng, Bin Zhu, Hongwen Yu, Wanglin Duan, Xiaohua Fang, Guanying Li, Shichang Liu\",\"doi\":\"10.7150/thno.114781\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p><b>Rationale</b>: Osteoarthritis (OA), a highly prevalent chronic degenerative joint disease, lacks truly effective therapies. Current approaches are limited by systemic toxicity, short drug half-lives, and insufficient efficacy. To address this, we developed an innovative therapeutic approach integrating the pharmacological benefits of nonsteroidal anti-inflammatory drugs (NSAIDs) with the mechanical support and localized delivery advantages of hydrogels. <b>Methods</b>: Various naproxen-peptide conjugates are designed and synthesized. These candidates were screened based on self-assembly behavior, biocompatibility and cyclooxygenase-2 (COX-2) inhibition. NpxFFK underwent further studies including assessment of anti-inflammatory activities and mechanism of action <i>in vitro</i>. <i>In vivo</i> therapeutic efficacy was evaluated in OA rat model using footprinting assay, micro-CT imaging, MRI imaging, histological staining, and immunohistochemistry. The therapeutic mechanism is explored via RNA sequencing. <b>Results</b>: Among naproxen-peptide conjugates NpxFFX (X = R, H, K, E) tested, NpxFFK demonstrated superior anti-inflammatory efficacy. It self-assembled into a stable hydrogel, exhibiting enhanced retention within the joint cavity and providing sustained anti-inflammatory action. <i>In vitro</i> studies revealed that NpxFFK effectively inhibited COX-2 activity, consequently suppressing key inflammatory factors (IL-1β, IL-6, IL-1, and TNF-α). Furthermore, it reprogramed macrophage polarization from M1 toward M2 and promoted chondrocyte proliferation. <i>In vivo</i> experiments demonstrate the NpxFFK hydrogel significantly mitigated articular degradation in OA rats, outperforming clinical treatments (naproxen treatment or hyaluronic acid treatment), thereby validating its therapeutic potential for OA. <b>Conclusions</b>: By integrating NSAID pharmacology with self-assembling peptide hydrogel delivery platform, we present a multifunctional strategy that significantly improves upon current OA treatments, underscoring its promise for translational healthcare innovation in OA management.</p>\",\"PeriodicalId\":22932,\"journal\":{\"name\":\"Theranostics\",\"volume\":\"15 17\",\"pages\":\"8779-8794\"},\"PeriodicalIF\":13.3000,\"publicationDate\":\"2025-08-11\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439141/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Theranostics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.7150/thno.114781\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Theranostics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.7150/thno.114781","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
Self-Assembling Hydrogels of Naproxen-Conjugated Peptides for Osteoarthritis Treatment.
Rationale: Osteoarthritis (OA), a highly prevalent chronic degenerative joint disease, lacks truly effective therapies. Current approaches are limited by systemic toxicity, short drug half-lives, and insufficient efficacy. To address this, we developed an innovative therapeutic approach integrating the pharmacological benefits of nonsteroidal anti-inflammatory drugs (NSAIDs) with the mechanical support and localized delivery advantages of hydrogels. Methods: Various naproxen-peptide conjugates are designed and synthesized. These candidates were screened based on self-assembly behavior, biocompatibility and cyclooxygenase-2 (COX-2) inhibition. NpxFFK underwent further studies including assessment of anti-inflammatory activities and mechanism of action in vitro. In vivo therapeutic efficacy was evaluated in OA rat model using footprinting assay, micro-CT imaging, MRI imaging, histological staining, and immunohistochemistry. The therapeutic mechanism is explored via RNA sequencing. Results: Among naproxen-peptide conjugates NpxFFX (X = R, H, K, E) tested, NpxFFK demonstrated superior anti-inflammatory efficacy. It self-assembled into a stable hydrogel, exhibiting enhanced retention within the joint cavity and providing sustained anti-inflammatory action. In vitro studies revealed that NpxFFK effectively inhibited COX-2 activity, consequently suppressing key inflammatory factors (IL-1β, IL-6, IL-1, and TNF-α). Furthermore, it reprogramed macrophage polarization from M1 toward M2 and promoted chondrocyte proliferation. In vivo experiments demonstrate the NpxFFK hydrogel significantly mitigated articular degradation in OA rats, outperforming clinical treatments (naproxen treatment or hyaluronic acid treatment), thereby validating its therapeutic potential for OA. Conclusions: By integrating NSAID pharmacology with self-assembling peptide hydrogel delivery platform, we present a multifunctional strategy that significantly improves upon current OA treatments, underscoring its promise for translational healthcare innovation in OA management.
期刊介绍:
Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.