Supramolecular coordination cages show a wide range of useful properties including, but not limited to, complex molecular machine‐like operations, confined space catalysis, and rich host–guest chemistries. Here we report the uptake and release of non‐covalently encapsulated, pharmaceutically‐active cargo from an octahedral Pd cage bearing polymer chains on each vertex. Six poly(ethylene glycol)‐decorated bipyridine ligands are used to assemble an octahedral Pd^II₆(TPT)₄ cage. The supramolecular container encapsulates progesterone and ibuprofen within its hydrophobic nanocavity and is activated by shear force produced by ultrasonication in aqueous solution entailing complete cargo release upon rupture, as shown by NMR and GPC analyses.