A microenvironment-responsive injectable hydrogel with core-shell nanoplatforms for sequential treatment of infected bone defects

Abstract

The treatment of infected bone defects remains a major clinical challenge because conventional therapies have limited efficacy against biofilm-associated infections and fail to effectively promote subsequent bone regeneration. In this study, an injectable self-healing hydrogel incorporating core–shell nanoparticles (AMCG NPs) with photothermal, catalytic, and microenvironment-responsive properties was developed. The AMCG NPs consisted of gold nanorod cores and copper peroxide-loaded mesoporous polydopamine shells functionalized with glycol chitosan. In the acidic infectious microenvironment, AMCG NPs were rapidly released from the hydrogel and efficiently penetrated the biofilm through pH-dependent charge conversion. Under NIR-II irradiation, the nanoparticles disrupted biofilm integrity through the synergistic effects of mild photothermal therapy and acid-responsive catalytic activity. Transcriptomic analysis further revealed that AMCG + NIR treatment disrupted bacterial copper homeostasis and aggravated oxidative stress, resulting in membrane damage, lipid peroxidation, and tricarboxylic acid cycle dysfunction, thereby contributing to bacterial death. Following infection control, low concentrations of Cu2+ promoted the formation of functional H-type vessels by upregulating CD31/EMCN expression, and further enhanced the osteogenic differentiation of BMSCs. This strategy enabled the sequential control of infection and promotion of vascularized bone regeneration, providing a promising therapeutic approach for infected bone defects.