Synergistic polyphosphate–gallic acid system heals infected skin defects by remodeling the immune microenvironment and restoring bioenergetics

Abstract

Infected skin defects persist in a pathological state characterized by dysregulation of the immune microenvironment and impaired bioenergetics, requiring coordinated treatment strategies to remold them. Currently developing therapies with coordinated effects are often hampered by incomplete targets, high complexity, and limited clinical performance, underscoring the need for minimalist yet effective strategies that integrate both targets. Here, we address this challenge by designing a two-component system, the polyphosphate–gallic acid (polyP-GA) complex, with high biocompatibility and adaptability to different material forms (e.g., solution, spray, hydrogel, and paste). Based on the mutually complementary and enhanced effects of the two constituents, the polyP-GA complex markedly inhibits bacterial infection, reduces reactive oxygen species (ROS) accumulation, and suppresses inflammation evidenced by facilitated macrophage polarization toward the reparative M2 phenotype and broad related anti-inflammatory transcriptional effects. Concurrently, the polyP-GA complex restores mitochondrial function and elevates intracellular adenosine triphosphate (ATP) levels, thereby activating pathways essential for fibroblast migration and angiogenesis. In a mouse model of infected skin defects, application of the polyP-GA complex (in the form of hydrogel and spray sequentially) significantly accelerated wound closure, enhanced collagen deposition and neovascularization, and promoted functional tissue remodeling. This work demonstrates that the minimalist therapeutic design, built on the synergistic pairing of biocompatible but otherwise subtherapeutic agents polyP and GA, can effectively break the cycle of infection-driven regenerative arrest, achieving high performance in promoting the healing of infected skin defects.