Engineering macrophage phenotype switching via nucleotide‐binding oligomerization domain‐like receptor protein 3 inflammasome inhibition: A translational approach using antibiotic cement for diabetic foot ulcers

Abstract

Diabetic foot ulcers (DFUs), a debilitating complication of diabetes, are exacerbated by persistent inflammation that disrupts wound repair. This study explores the therapeutic potential of antibiotic‐loaded bone cement (ALBC) in modulating NLRP3 inflammasome activation and macrophage polarization to resolve chronic inflammation and accelerate healing. Using db/db diabetic mice with dorsal wounds and RAW264.7 macrophages under high‐glucose conditions, we tested graded ALBC doses (high‐dose ALBC, low‐dose ALBC, and medium‐dose ALBC) both in vivo and in vitro. Multi‐modal analyses—including cytokine profiling (enzyme‐linked immunosorbent assay), macrophage phenotyping (flow cytometry/immunofluorescence), and molecular pathway interrogation (reverse transcription quantitative PCR/Western blot)—revealed that ALBC dose‐dependently suppressed NLRP3 inflammasome assembly, reduced IL‐1β/IL‐18 secretion, and skewed macrophages toward anti‐inflammatory M2 phenotypes. Pharmacological NLRP3 activation reversed these effects, confirming pathway specificity. ALBC‐treated wounds exhibited accelerated re‐epithelialization, collagen deposition, and angiogenesis, correlating with attenuated systemic inflammation. Crucially, clinical DFU samples mirrored preclinical findings, showing NLRP3 downregulation and M2 dominance in ALBC‐responsive cases. These results demonstrate that ALBC orchestrates immunometabolic reprogramming by silencing NLRP3‐driven inflammation and fostering pro‐reparative macrophage responses. By bridging biomaterial engineering with immunomodulation, this work advances a translatable strategy for refractory DFU management, offering a dual‐action therapeutic platform that combines localized antibiotic delivery with microenvironmental immune reset.