Authors
Zhongqi Yao, Ningning Yue, Mingfei Chen, Changping Wang, Yiyun Cheng, Hui Wang
Published in
Journal of controlled release : official journal of the Controlled Release Society. Pages 115438. Oct 06, 2026. Epub Oct 06, 2026.
Abstract
Cyclic squaramide oligomers are attractive supramolecular building blocks, but their use as biomolecular delivery materials remains underexplored. Here, we report the one-step preparation of a low-molecular-weight cyclic oligomeric squaramides (COS) mixture by equimolar condensation of dimethyl squarate and 2,2'-diamino-N-methyldiethylamine. Reaction-condition studies and comparative DFT-refined scan calculations indicate that linker architecture and competing hydrogen-bonding interactions influence cyclic oligomer formation. In aqueous buffer, COS forms dynamic supramolecular assemblies and associates noncovalently with copper‑zinc superoxide dismutase (SOD). The COS/SOD complexes preserved SOD activity during complexation and retained more than 70% activity after 1 h in simulated gastric fluid, whereas free SOD retained less than 20%. Their pH-dependent surface-charge change was accompanied by greater transport through mucus than a cationic formulation control. In HT-29 epithelial cells and RAW264.7 macrophages, COS/SOD increased intracellular SOD-associated fluorescence, reduced reactive oxygen species and mitochondrial dysfunction, and suppressed pro-inflammatory responses. Following oral administration in dextran sulfate sodium-induced colitis, COS/SOD improved disease activity, colon morphology, inflammatory markers, and intestinal barrier-associated outcomes. These findings position self-assembling cyclic squaramide oligomers as a supramolecular platform for oral protein formulation and delivery.
PMID:
42838454
Bibliographic data and abstract were imported from PubMed on 07 Oct 2026.
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