Significance Despite considerable advances in de novo protein design in recent years, it still remains challenging to engineer proteins with large internal cavities that can be functionalized to become biotechnological tools, such as specific binders, sensors, or catalysts. In this work, we outline a computational strategy to combine multiple de novo designed domains into symmetric protein assemblies that enclose large internal chambers. The high stability of de novo scaffolds enables ready functionalization of these chambers; for instance, with specific metal-binding sites, as demonstrated here by generating a lanthanide-binding protein with ultra-high affinity.