A Bioinspired Nanozyme Enables Glycoimmune Therapy via Precision Sialoglycan Trimming

Abstract

ABSTRACT Aberrant sialoglycan–Siglec interactions constitute an emerging glycoimmune checkpoint driving tumor immune evasion, yet selective intervention remains challenging for current cancer immunotherapies. Existing strategies, including Siglec blockade and sialidase treatment, are constrained by instability, immunogenicity, and limited tumor targeting. Here we report a molecularly imprinted nanobiomimetic enzyme (MINBE) that integrates a template‐defined catalytic pocket with a pH‐responsive protective inorganic‐polymer architecture, enabling selective editing of tumor‐associated sialic acids and immune modulation. MINBE is engineered utilizing a sialic acid‐containing disaccharide template to encode an imprinted catalytic nanocore, while inorganic scaffolds and polymer shielding enhance stability during systemic circulation. In the acidic tumor microenvironment, the pH‐responsive inorganic layer dissociates to expose its hydrolytic core for desialylation, thereby disrupting sialoglycan–Siglec signaling. Concomitantly, this activation is accompanied by the release of Mn ions, which promote dendriticcell activation. Both in vitro assays and in vivo studies in tumor‐bearing mice showed efficient tumor desialylation and pronounced tumor growth inhibition. This molecular imprinting encoded design provides a generalizable strategy for programmable sialoglycan editing, with potential applicability to modulate glyco‐immune checkpoints across tumor types and other glycan‐driven processes beyond cancer.