<p>The discovery of buckminsterfullerene (C₆₀) marked a milestone in exploring three-dimensional carbon materials. However, with the exponential increase in the number of isomers for higher fullerenes, it has become challenging to realize the enrichment of the isomers by molecular recognition. Here we report two pseudo-cubic metal–organic cages, <i>T</i> and <i>S</i>₄, with distinct cavity microenvironments, that showcase recognition specificity towards higher fullerene isomers. Compared with cage <i>T</i>, a symmetry shift from <i>S</i>₄ to <i>C</i>₂ emerges upon encapsulating an ellipsoidal <i>D</i>₂-C₇₆ guest, owing to the precise shape matching that curtails guest rotation. Furthermore, the low-symmetry cage <i>S</i>₄ shows exceptional sensitivity in distinguishing between closely related isomers, such as a pair of <i>C</i>_2<i>v</i>-symmetric C₇₈ isomers, and shows promise for the selective enrichment of higher fullerenes. The approach of reducing symmetry positions metal–organic cages as promising candidates for encapsulating and identifying a broader spectrum of fullerene isomers, paralleling the specificity observed in biological systems.</p><p></p>