Yeruva Taj, Yang Sydney, Kaluzienski Michele, Louisthelmy Rebecca, Doski Shadin, Maisel Katharina, Duncan Gregg A
Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA.
bioRxiv. 2025 Aug 21:2025.08.15.670558. doi: 10.1101/2025.08.15.670558.
Inflammatory bowel disease (IBD) is a chronic condition characterized by recurrent gastrointestinal inflammation that requires long-term therapeutic intervention. While anti-TNF-α monoclonal antibodies (mAbs) are effective in maintaining remission in IBD, systemic delivery is associated with immunosuppression, poor targeting efficiency, and high cost. To address these limitations, we developed a synthetic mucin-based hydrogel for localized delivery of TNF-α-targeting mAbs. Mucins are heavily glycosylated biopolymers that naturally bind antimicrobial and anti-inflammatory proteins, making them well-suited for local biologic drug delivery at mucosal sites. Synthetic mucin-based hydrogels were formed by crosslinking mucin harvested from porcine small intestine with a 4-arm PEG-thiol and loaded with mAbs to evaluate biocompatibility, antibody release kinetics, and therapeutic efficacy. studies confirmed cytocompatibility of mucin-based hydrogels and demonstrated sustained release of full-length IgG antibodies, with enhanced release under proteolytic conditions simulating the gastrointestinal environment. Moreover, mucin-based hydrogels alone were found to modulate macrophage activation and dampen inflammation in LPS-stimulated macrophages. Treatment of LPS-stimulated macrophages with mAb-loaded hydrogels reduced pro-inflammatory cytokine production and macrophage activation, confirming retention of mAb bioactivity. Compared to antibodies administered in solution, biodistribution studies revealed greater absorption of antibodies when loaded in mucin-based hydrogels and administered via enema in TNBS-induced colitis mice likely due to enhanced adhesion to mucosal epithelium and slowed intestinal clearance. This study demonstrates the potential of mucin-based hydrogels as a platform for local mAb delivery in IBD, enabling targeted immunosuppression while minimizing systemic exposure.
炎症性肠病（IBD）是一种慢性疾病，其特征为反复出现的胃肠道炎症，需要长期的治疗干预。虽然抗TNF-α单克隆抗体（mAb）在维持IBD缓解方面有效，但全身给药会导致免疫抑制、靶向效率低和成本高。为了解决这些局限性，我们开发了一种基于合成粘蛋白的水凝胶，用于局部递送靶向TNF-α的mAb。粘蛋白是高度糖基化的生物聚合物，天然结合抗菌和抗炎蛋白，使其非常适合在粘膜部位进行局部生物药物递送。通过将从猪小肠收获的粘蛋白与四臂PEG-硫醇交联形成基于合成粘蛋白的水凝胶，并加载mAb以评估生物相容性、抗体释放动力学和治疗效果。研究证实了基于粘蛋白的水凝胶的细胞相容性，并证明了全长IgG抗体的持续释放，在模拟胃肠道环境的蛋白水解条件下释放增强。此外，发现单独的基于粘蛋白的水凝胶可调节巨噬细胞活化并减轻LPS刺激的巨噬细胞中的炎症。用负载mAb的水凝胶处理LPS刺激的巨噬细胞可减少促炎细胞因子的产生和巨噬细胞活化，证实了mAb生物活性的保留。与溶液中给药的抗体相比，生物分布研究表明，在TNBS诱导的结肠炎小鼠中，当负载在基于粘蛋白的水凝胶中并通过灌肠给药时，抗体的吸收更大，这可能是由于对粘膜上皮的粘附增强和肠道清除减慢。这项研究证明了基于粘蛋白的水凝胶作为IBD中局部mAb递送平台的潜力，能够实现靶向免疫抑制，同时最大限度地减少全身暴露。
