Crystal Facet‐Polysaccharide Matching in CFS‐P Nanocrystals Drives Fungal Uptake, Vacuole Destruction, and Selective Antifungal Activity

ABSTRACT The lack of selective antifungal agents remains a major clinical challenge. Here, we discover facet‐polysaccharide matching between polyvinylpyrrolidone‐directed tetragonal CuFeSe ₂ nanocrystals (CFS‐P) and fungi drives ultrapotent and highly selective fungicidal activity. High‐index facets uniquely exposed on CFS‐P show markedly enhanced affinity for mannan, the dominant polysaccharide of the fungal outer cell wall, as validated by DFT, molecular dynamics, and calorimetry. Mannan recognition promotes efficient fungal internalization of CFS‐P and its preferential accumulation in vacuoles, leading to vacuolar cavitation, calcium overload, mitochondrial hyperpolarization, and transcriptional reprogramming of metal and vacuole‐associated pathways. CFS‐P achieves therapeutic efficacy comparable to amphotericin B while exhibiting superior mammalian biocompatibility. This work reveals a previously unrecognized wall‐vacuole disruptive antifungal mechanism and enlightens the exploration of facet‐encoded biological recognition in anti‐infective design.