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

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. <i>In vitro</i>, 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.