The dodecahedral capsid formed by Aquifex aeolicus lumazine synthase (AaLS) is a promising protein scaffold for bionanotechnological applications. A cysteine was installed at the inner surface of the AaLS capsid to give a variant (AaLS-IC) that can covalently capture small-molecule thiols in its hollow interior. Cargo loading utilizes a two-stage thiol–disulfide exchange process, involving the initial formation of an activated disulfide adduct between AaLS-IC and 2-nitro-5-thiobenzoate (NTB) followed by displacement of the NTB by an incoming guest molecule. Using a thiol-containing curcumin derivative (cur-SH) as a model guest, we show that about 41 guest molecules can be loaded per capsid. The sequestration of cur-SH inside the capsid increases its solubility in aqueous buffer by more than 30-fold. Further, the guest can be released upon treatment with tris(2-carboxyethyl)phosphine, which reduces the disulfide bond tethering cur-SH to the capsid. Thus, the AaLS-IC capsid can act as a container for small-molecule thiols, and guest release can be triggered by reducing agents.