A Receptor‐Mediated Endolysosomal Recycling Chimera Enables Catalytic TNF‐α Degradation for Sustained Treatment of Mucosal Inflammation

Vollständiger Abstract

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ABSTRACT Mucosal inflammatory disorders such as dry eye disease (DED) and inflammatory bowel disease (IBD), driven by TNF‐α‐mediated immune‐epithelial crosstalk, remain therapeutically challenging. Conventional inhibitors often suffer from poor mucosal permeability and transient efficacy with 1:1 binding. Although extracellular protein degradation (eTPD) technologies can eliminate pathogenic proteins, most of them operate stoichiometrically, limiting dosage efficiency and durability. Here, we report a receptor‐mediated endolysosomal recycling chimera (RECYC) platform that enables catalytic, recyclable degradation of TNF‐α with multiple turnovers, achieving sustained suppression of mucosal inflammation. RECYC integrates a pH‐responsive peptide that binds TNF‐α at physiological pH and releases it in acidic endosomes, with a CI‐M6PR‐targeting aptamer that remains pH‐stable to drive continuous recycling. The anti‐TNF‐α RECYC achieved efficient uptake and recyclable clearance of extracellular TNF‐α across conjunctival and colonic epithelial cells and macrophages, achieving superstoichiometric TNF‐α clearance with up to 7.5 catalytic turnovers. The ∼30 kDa RECYC exhibited superior tissue penetration in murine cornea and colon compared to inhibitory antibodies. In murine DED and IBD models, RECYC restored ocular surface homeostasis and reduced colon inflammation with low‐dose, infrequent administration. Human corneal limbus organoids further confirmed prolonged anti‐inflammatory activity. Together, RECYC establishes a modular, recyclable eTPD platform for sustained treatment of TNF‐α‐driven mucosal inflammation.