Chem. Sci., 2025, Accepted Manuscript DOI: 10.1039/D5SC04624F, Edge Article Ruiwen Wang, Wei-guo Yang, Mingli Su, Jia-Min Qin, Jia-Qi Liu, Xiao-Han Yan, Jun-Yi Cao, Ruo Yuan, Ying Zhuo, Ming Chen, Chaoyong Yang, Wenbin Liang Small-molecule drugs, constituting over 60% of FDA-approved therapeutics (2017–2022), face unresolved challenges in elucidating intracellular mechanism. We present a dual-strategy platform integrating “In Silico Aptamer Affinity Maturation” (ISAAM) and “Structural...