Polyoxometalates enable cellular uptake of the actin-binding toxin phalloidin.

Superchaotropic inorganic cluster anions can transport membrane-impermeable biomolecules across lipid bilayers, yet how carrier structure governs delivery efficiency remains unclear. Here we show that two closely related Keggin-type polyoxometalates (POMs)-[SiW12O40]4- (SiW12) and its mono-molybdenum-substituted analogue [SiMoW11O40]4- (SiMoW11)-differ markedly in their efficiency to deliver phalloidin, a rigid membrane-impermeable F-actin probe, into colorectal carcinoma cells. Despite near-identical size, charge, and charge density, SiW12 undergoes extensive hydrolysis at pH 7.5 while SiMoW11 shows only partial spectral reorganisation indicative of structural rearrangement, as established by 183W NMR spectroscopy. The direct quantitative comparison of the two compounds in cell culture medium was not accessible, due to the inherent lack of sensitivity that exists in 183W NMR under these conditions. Both POMs are non-toxic up to 100 µM and facilitate phalloidin uptake and F-actin staining in two human colorectal carcinoma cell lines (HCT116 and HT29), with SiMoW11 delivering phalloidin more effectively than SiW12 at equivalent carrier and cargo concentrations.