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

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.