Structurally reprogrammed modified citrus pectin (MCP) enables potentiated galectin-3 sequestration and injectable carboxymethyl chitosan/berberine hydrogel construction for osteoarthritis immunotherapy

IF 10.2 1区 医学 Q1 ENGINEERING, BIOMEDICAL
Chi Lin , Fwu-Long Mi , Chia-Yun Cha , Fang-Yu Hsu , Siti Ayu Ulfadillah , Min-Lang Tsai , Hsien-Tsung Lu
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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.

Abstract Image

结构重编程修饰的柑橘果胶(MCP)能够增强半乳糖凝集素-3的隔离和可注射的羧甲基壳聚糖/小檗碱水凝胶构建,用于骨关节炎的免疫治疗
由于缺乏能够阻止疾病进展的有效治疗方法,骨关节炎(OA)仍然是一个主要的临床挑战。慢性滑膜炎症和软骨退化是其标志性特征,其中半乳糖凝集素-3 (Gal-3),一种β-半乳糖苷结合凝集素,通过驱动M1巨噬细胞激活和软骨细胞凋亡起着关键的上游作用。改性柑橘果胶(MCP)是一种天然的Gal-3粘合剂,具有治疗潜力,但被快速清除和有限的关节保留所阻碍。在此,我们提出氧化MCP (oxMCP),结构上重新编程的MCP,其功能是gal -3隔离和交联矩阵。这种转化是通过高酸盐氧化实现的,该氧化过程引入了双醛基团,使其与N, o -羧甲基壳聚糖(NOCC)进行希夫碱交联,同时通过降低分子量、增加链柔韧性和暴露β-(1→4)-半乳糖基序来增强Gal-3的亲和力。这些变化显著增强了gal -3相关的生物活性,包括M1巨噬细胞抑制和软骨保护。得到的oxMCP/NOCC水凝胶进一步与具有m2极化活性的阳离子生物碱小檗碱(BBR)结合,通过非共价相互作用增强了水凝胶网络,增强了m2极化能力。oxMCP/NOCC/BBR水凝胶具有优异的自愈性、低肿胀、缓慢降解和持续的药物释放,这是关节内给药的关键特征。在体外,它抑制氧化应激、基质降解和软骨细胞凋亡,同时促进巨噬细胞向M2表型极化。在体内,关节内给药减轻了大鼠OA模型的滑膜炎症和软骨保护。这项工作将MCP从短效的Gal-3阻断剂转变为具有免疫调节和软骨保护能力的持久、生物活性增强的治疗平台,为局部病理适应性OA干预提供了一种转变策略。
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来源期刊
CiteScore
8.30
自引率
4.90%
发文量
303
审稿时长
30 days
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).
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