Mechanochemical Activation of Biodegradable High‐Entropy Materials Enables Immune‐Synergistic Therapy for Deep‐Seated and Drug‐Resistant Infections

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High‐entropy materials (HEMs) offer compositional diversity and tunable physicochemical properties for catalysis and biophotonics applications, yet their translation is limited by poor biodegradability and restricted penetration depth of light‐dependent activation. In this study, a biodegradable layered double hydroxide–like high‐entropy material (LDH‐HEM) composed of Fe, Cu, Zn, Mn, and Al is reported as an ultrasound‐activated sonosensitizer for eradicating Pseudomonas aeruginosa ( P. aeruginosa ) infections. Experimental evidence and theoretical analysis collectively reveal that the multi‐metal synergy effectively narrows the bandgap and enhances exciton generation under ultrasound excitation, while ultrasonic pressure‐induced lattice distortion enables a strain‐driven autonomous type‐II heterojunction that promotes charge separation. Under mild ultrasound (1.0 MHz, 0.5 W cm −2 , 10 min) stimulation, LDH‐HEM generates abundant reactive oxygen species, achieving >99% eradication of P. aeruginosa at a low dosage (50 µg mL −1 ). In addition, LDH‐HEM reprograms macrophage polarization toward an M1 phenotype, thereby boosting bacterial phagocytosis and clearance. In murine models of subcutaneous abscesses and bacterial keratitis infected with P. aeruginosa , LDH‐HEM‐mediated sonodynamic therapy effectively eradicates pathogens and accelerates wound and corneal healing within 2 weeks. This work introduces a mechanochemically responsive and biodegradable high‐entropy platform for deep‐seated infection therapy and provides design principles for engineering multifunctional HEMs for biomedical translation.