A GSH-scavenging and synthesis-blocking microneedle patch for augmenting photodynamic eradication of diabetic wound biofilms

Abstract

Infected diabetic wounds represent a significant clinical challenge, largely due to persistent bacterial biofilm infection that impedes the healing process. Photodynamic therapy (PDT), an emerging antibiofilm strategy, uses photosensitizers to generate reactive oxygen species (ROS) upon illumination, which oxidatively destroy bacteria and thus combat biofilm-associated infections. Nevertheless, the efficacy of PDT is substantially undermined by restricted ROS diffusion through compact biofilm structures and rapid ROS neutralization by overexpressed reduced glutathione (GSH) within the biofilm microenvironment. Current GSH-depletion strategies predominantly focus on eliminating pre-existing GSH, leaving the critical issue of its continuous synthesis unaddressed. To overcome this limitation, we developed a GSH-scavenging and synthesis-blocking microneedle patch (MN/CuTCPP@BSO) for the enhanced photodynamic eradication of diabetic wound biofilms. The patch incorporates the GSH synthesis inhibitor L-buthionine sulfoximine (BSO) onto copper-tetrakis(4-carboxyphenyl)porphyrin (CuTCPP) nanosheets. We demonstrate that CuTCPP effectively eliminates the overexpressed GSH in the biofilm, while BSO concurrently blocks its production. This dual-pathway suppression of the bacterial antioxidant system synergistically minimizes ROS clearance. Furthermore, the microneedle platform ensures deep penetration of therapeutic agents into the biofilm. In vitro and in vivo evaluations collectively verify that MN/CuTCPP@BSO potently enhances ROS generation, effectively eradicates the biofilm, and promotes wound healing through Cu²⁺-mediated angiogenesis, offering a robust and safe strategy for treating biofilm infections in diabetic wounds.