The development of efficient solar energy conversion is one of the grand challenges of our time. Water splitting, or the disproportionation of H2O into energy-dense fuels, H2 and O2, is undoubtedly a promising strategy. We have used a closed-loop materials design process to develop a new class of nanoscale heterostructures comprising MxV2O5 nanowires, where M is a p-block cation characterized by a stereoactive lone pair of electrons and x is its stoichiometry, interfaced with II−VI semiconductor quantum dots (QDs). Our signature theoretical design and experimental realization of SnxV2O5 as a hole acceptor mitigates the longstanding problem of photocorrosion of quantum dots and provides a powerful demonstration of using mid-gap states derived from lone-pairs of p-block cations as acceptors of photogenerated holes.