LAUSR

Biotoxins are diverse, complex, and hypertoxic, ultimately serving as grave and lasting menaces to humanity. Here, it is aimed to introduce a new detoxification methodology for macromolecular biotoxin through complexation by a very large macrocycle. A 25‐mer peptide isolated from Lycosa erythrognatha spider venom (LyeTxI) is selected as the model macromolecular biotoxin. Quaterphen[4]arene, with a side length of ≈1.6 nm, has a sufficient cavity to bind LyeTxI. Hence, the water‐soluble derivative of Quaterphen[4]arene (H) is designed and synthesized. H exhibits an overall host–guest complexation toward LyeTxI, resulting in a considerably high association constant of (7.01 ± 0.18) × 107 m−1. This encapsulation of peptide is interesting as traditional macrocycles can only engulf the amino acid residues of peptides due to their limited cavity size. In vitro assay verifies that complexation by H inhibits the interactions of LyeTxI with cell membranes, thereby reducing its cytotoxicity, suppressing hemolysis, and decreasing the release of lactate dehydrogenase. Notably, the intravenous administration of H has a significant therapeutic effect on LyeTxI‐poisoned mice, alleviating inflammation and tissue damage, and markedly improving the survival rate from 10% to 80%. An efficient and potentially versatile approach is provided to detoxify macromolecular biotoxins, with giant macrocycle serving as an antidote.