Chem. Sci., 2025, Accepted Manuscript DOI: 10.1039/D5SC05468K, Edge Article Guofu Zhong, Lin Fan, Pengyang Wang, Chang He, Xiaoyu Chen, Linlong Dai, Daokai Xiong Enhancing drug efficacy often involves increasing the proportion of sp³-hybridized carbons. Three-dimensional polycyclic frameworks, such as bicyclo[1.1.1]pentanes (BCPs) and bicyclo[2.1.1]hexanes (BCHs), serve as excellent benzene bioisosteres, improving bioavailability and reducing...