Abstract Background Idiopathic pulmonary fibrosis is a fatal interstitial lung disease characterized by persistent inflammation, excessive extracellular matrix (ECM) deposition, and progressive tissue scarring. The limited efficacy of single-target therapies, such as the anti-CTGF (connective tissue growth factor) monoclonal antibody FG3019, underscores the urgent need for combinatorial strategies that simultaneously address multiple pathogenic pathways. Objective This study aimed to design and evaluate a novel multifunctional biomaterial system that synergistically combines anti-inflammatory action, ECM degradation, and targeted inhibition of CTGF for the treatment of pulmonary fibrosis. Methods An anti-inflammatory microsphere was constructed by conjugating gelatin with an optimized Astragalus polysaccharide (APS, 10 kDa, glucan) fraction, identified and structurally characterized via gel permeation chromatography, high performance liquid chromatography (HPLC), and methylation analysis. These microspheres were further functionalized by loading with matrix metalloproteinase 19 (MMP19) to create a dual-action material capable of both mitigating inflammation and degrading ECM. The critical role of CTGF C-terminal (CT) domain was validated using CTGF heterozygous knockout mice. The fibrogenic potential of this domain was confirmed by exogenous administration. A specific nucleic acid aptamer was subsequently developed to target this domain. The dual-functional microspheres were integrated with the CTGF CT-domain-specific aptamer to form a tri-component therapeutic system. The synergistic therapeutic efficacy of this composite was systematically evaluated in a bleomycin-induced murine model of pulmonary fibrosis. Results The APS-gelatin microspheres significantly suppressed key inflammatory mediators, notably reducing iNOS and TNF-α levels compared to plain gelatin controls. The incorporation of MMP19 successfully decreased the established COL1A1 and FN1. The bleomycin-induced pulmonary fibrosis and inflammation level was significantly downregulated by CTGK knockout, which could be rescued by CTGF DIV intraperitoneally administration. Moreover, aptamer treatment blocked the pro-fibrotic effect of CTGF DIV. Further, the tri-component composite system produced a synergistic therapeutic outcome. It most effectively downregulated the content of major fibrotic markers, including inflammatory and fibrotic mediators TGFβ and iNOS, as well as inhibited the expression of COL1A1 and FN1. Critically, this molecular and histological improvement translated to significant functional recovery. Mice treated with the full composite system exhibited a near-complete restoration of lung compliance and vital capacity, outperforming all partial-treatment control groups. Conclusion Collectively, the tri-component composite material exhibited a synergistic therapeutic effect, significantly outperforming any single-component therapy in mitigating pathological injury and reducing collagen deposition. This abstract is funded by: Research Grants Council
Xu et al. (Fri,) studied this question.