Many biological processes are driven by the interaction of a host with a guest molecule. We show such interactions can be modulated by carefully defining the local molecular environment to give a specific chemical outcome. Particularly, the selectivity of a host toward two different ions (Ca²⁺ and Al³⁺) is defined by it being in solution or the physisorbed state. In solution, the host displays greater selectivity toward Ca²⁺. When physisorbed, the selectivity profile of the host is reversed with enhanced binding of Al³⁺. This demonstrates a single host molecule can be tailored to selectively bind multiple guests by altering its nanoenvironment.