Chi Lin , Fwu-Long Mi , Chia-Yun Cha , Fang-Yu Hsu , Siti Ayu Ulfadillah , Min-Lang Tsai , Hsien-Tsung Lu
{"title":"Structurally reprogrammed modified citrus pectin (MCP) enables potentiated galectin-3 sequestration and injectable carboxymethyl chitosan/berberine hydrogel construction for osteoarthritis immunotherapy","authors":"Chi Lin , Fwu-Long Mi , Chia-Yun Cha , Fang-Yu Hsu , Siti Ayu Ulfadillah , Min-Lang Tsai , Hsien-Tsung Lu","doi":"10.1016/j.mtbio.2025.102330","DOIUrl":null,"url":null,"abstract":"<div><div>Osteoarthritis (OA) remains a major clinical challenge due to the lack of effective treatments capable of halting disease progression. Chronic synovial inflammation and cartilage degradation are hallmark features, wherein galectin-3 (Gal-3), a β-galactoside-binding lectin, plays a pivotal upstream role by driving M1 macrophage activation and chondrocyte apoptosis. Modified citrus pectin (MCP), a natural Gal-3 binder, possesses therapeutic potential but is hindered by rapid clearance and limited joint retention. Herein, we present oxidized MCP (oxMCP), structurally reprogrammed MCP, that functions as a Gal-3-sequestering and crosslinkable matrix. This transformation was achieved via periodate oxidation, which introduced dialdehyde groups for Schiff base crosslinking with N, O-carboxymethyl chitosan (NOCC), while simultaneously enhancing Gal-3 affinity by reducing the molecular weight, increasing the chain flexibility, and exposing β-(1 → 4)-galactan motifs. These changes markedly amplified Gal-3-associated bioactivities, including M1 macrophage suppression and chondroprotection. The resulting oxMCP/NOCC hydrogel was further integrated with berberine (BBR), a cationic alkaloid with M2-polarizing activity, which reinforced the hydrogel network via non-covalent interactions and empowered the M2-polarizing capacity. The oxMCP/NOCC/BBR hydrogel exhibited excellent self-healing, low swelling, slow degradation, and sustained drug release, key features for intra-articular delivery. <em>In vitro</em>, it suppressed oxidative stress, matrix degradation, and chondrocyte apoptosis while promoting macrophage polarization toward the M2 phenotype. In vivo, intra-articular administration alleviated synovial inflammation and preserved cartilage in a rat OA model. This work transformed MCP from a short-acting Gal-3 blocker into a durable, bioactivity-enhanced therapeutic platform with immunomodulatory and cartilage-protective capabilities, offering a transformative strategy for a localized pathology-adaptive OA intervention.</div></div>","PeriodicalId":18310,"journal":{"name":"Materials Today Bio","volume":"35 ","pages":"Article 102330"},"PeriodicalIF":10.2000,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Materials Today Bio","FirstCategoryId":"5","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2590006425009019","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENGINEERING, BIOMEDICAL","Score":null,"Total":0}
引用次数: 0
Abstract
Osteoarthritis (OA) remains a major clinical challenge due to the lack of effective treatments capable of halting disease progression. Chronic synovial inflammation and cartilage degradation are hallmark features, wherein galectin-3 (Gal-3), a β-galactoside-binding lectin, plays a pivotal upstream role by driving M1 macrophage activation and chondrocyte apoptosis. Modified citrus pectin (MCP), a natural Gal-3 binder, possesses therapeutic potential but is hindered by rapid clearance and limited joint retention. Herein, we present oxidized MCP (oxMCP), structurally reprogrammed MCP, that functions as a Gal-3-sequestering and crosslinkable matrix. This transformation was achieved via periodate oxidation, which introduced dialdehyde groups for Schiff base crosslinking with N, O-carboxymethyl chitosan (NOCC), while simultaneously enhancing Gal-3 affinity by reducing the molecular weight, increasing the chain flexibility, and exposing β-(1 → 4)-galactan motifs. These changes markedly amplified Gal-3-associated bioactivities, including M1 macrophage suppression and chondroprotection. The resulting oxMCP/NOCC hydrogel was further integrated with berberine (BBR), a cationic alkaloid with M2-polarizing activity, which reinforced the hydrogel network via non-covalent interactions and empowered the M2-polarizing capacity. The oxMCP/NOCC/BBR hydrogel exhibited excellent self-healing, low swelling, slow degradation, and sustained drug release, key features for intra-articular delivery. In vitro, it suppressed oxidative stress, matrix degradation, and chondrocyte apoptosis while promoting macrophage polarization toward the M2 phenotype. In vivo, intra-articular administration alleviated synovial inflammation and preserved cartilage in a rat OA model. This work transformed MCP from a short-acting Gal-3 blocker into a durable, bioactivity-enhanced therapeutic platform with immunomodulatory and cartilage-protective capabilities, offering a transformative strategy for a localized pathology-adaptive OA intervention.
期刊介绍:
Materials Today Bio is a multidisciplinary journal that specializes in the intersection between biology and materials science, chemistry, physics, engineering, and medicine. It covers various aspects such as the design and assembly of new structures, their interaction with biological systems, functionalization, bioimaging, therapies, and diagnostics in healthcare. The journal aims to showcase the most significant advancements and discoveries in this field. As part of the Materials Today family, Materials Today Bio provides rigorous peer review, quick decision-making, and high visibility for authors. It is indexed in Scopus, PubMed Central, Emerging Sources, Citation Index (ESCI), and Directory of Open Access Journals (DOAJ).