Photothermal nanomedicine based on self-assembly of biological components, with excellent biosafety and customized performance, is vital significance for precision cancer therapy. However, the programmable design of photothermal nanomedicine remains extremely challenging due to the vulnerability and variability of noncovalent interactions governing supramolecular self-assembly. Herein, it is reported that amino acid encoding is a facile and potent means to design and construct supramolecular photothermal nanodrugs with controlled therapeutic activities. It is found that the amount and type of amino acid dominates the assembled nanostructures, structural stability, energy-conversion pathway, and therapeutic mechanism of the resulting nanodrugs. Two optimized nanodrugs are endowed with robust structural integrity against disassembly along with high photothermal conversion efficiency, efficient cellular internalization, and enhanced tumor accumulation, which result in more efficient tumor ablation. This work demonstrates that design based on amino acid encoding offers an unprecedented opportunity for the construction of remarkable photoactive nanomedicines toward cancer diagnostics and therapeutics.