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.