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.

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.