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However, balancing selectivity, reactivity, and potency is essential for safe and effective drugs. Here, we employ a cell\u2010selective bioorthogonal prodrug design to enhance the selectivity for covalent inhibitors without compromising the reactivity and potency. The upregulation of phosphatase and integrin facilitates the formation of enzyme\u2010instructed supramolecular assemblies (EISA) on the cancer cell membrane. These assemblies localize bioorthogonal reaction handles tetrazine (Tz), which liberate Melphalan from its bioorthogonal prodrug TCO\u2010Mel. The TCO modification disrupts the LAT1\u2010mediated transportation, reducing cellular permeability of TCO\u2010Mel and the corresponding cytotoxicity to normal cells. Although the cell\u2010selective on\u2010membrane assemblies directed prodrug activation restores Melphalan influx to inhibit cancer cell growth. 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