Criteria for Justifying High-Entropy Complexity in Catalytic Cancer Therapy

Abstract High-entropy nanomaterials (HEMs) are advancing catalytic cancer therapy. The prevailing view treats entropy as a performance-enhancing design parameter, assuming it improves activity by broadening active-site chemistries. This review reframes that view as an oversimplification, positioning entropy as a contingent design variable realized only when it resolves durability or robustness limitations beyond lower-entropy materials, not as a general-purpose performance multiplier. Tumor microenvironment constraints—acidity, hypoxia, redox imbalance, and glutathione abundance—limit conventional nanoagents' durability. Under such constraints, entropy-stabilized atomic heterogeneity can generate distributed active sites, electronic delocalization, and resistance to thiol-induced deactivation, enabling functional coexistence beyond compositional additivity. Multifunctionality introduces trade-offs: reduced selectivity, uncontrolled reactive oxygen species generation, and active-site interference. HEMs are justified only when entropy is essential for catalytic persistence under competing biological constraints, not when it merely correlates with improved activity in a single assay. Rigorous benchmarks—phase stability, durability, and lower-entropy comparators—should guide design toward safe, translational deployment.