Pore space partitioning (PSP) is methodically suited for dramatically increasing the density of guest binding sites, leading to the partitioned acs (pacs) platform capable of record-high uptake for CO₂ and small hydrocarbons such as C₂H_x. For gas separation, achieving high selectivity amid PSP-enabled high uptake offers an enticing prospect. Here we aim for high selectivity by introducing the bioisosteric (BIS) concept, a widely used drug design strategy, into the realm of pore-space-partitioned MOFs. New pacs materials have high C₂H₂/CO₂ selectivity of up to 29, high C₂H₂ uptake of up to 144 cm³/g (298 K, 1 atm), and high separation potential of up to 5.3 mmol/g, leading to excellent experimental breakthrough performance. These metrics, coupled with exceptional tunability, high stability, and low regeneration energy, demonstrate the broad potential of the BIS-PSP strategy.