Binary drug combinations often target different pathways for cooperative therapy. This study explores synergistic cooperativity between crystal growth modifiers binding to the same site to prevent calcium oxalate monohydrate (COM) crystallization, a major component of kidney stones. The authors found that combining citrate with natural polyphenols (gallic acid, ellagic acid, pyrogallic acid, or protocatechuic acid) boosted inhibitory efficacy up to fourfold compared to citrate alone. Experimental and simulation techniques revealed synergy in suppressing COM growth, reducing growth kinetic constants, and suppressing crystallization driving force. *In vitro* and *in vivo* studies demonstrated synergistic reductions in crystal-cell interactions, renal calcium oxalate deposition, and kidney injury, suggesting an effective therapeutic strategy for kidney stone prevention.

Si Li, Donghui Zhou, Zuoxuan Zhu, Xiaoyue Tan, Weiwei Tang, Junbo Gong