Au Nanoparticle-Functionalized Antheraea pernyi Silk Nanofibrils: A Spatially Adaptive Anti-Inflammatory and Pro-Regenerative Paradigm for Disparate Chronic Epithelial Diseases

Abstract Management of disparate chronic epithelial diseases relies on fragmented site-specific protocols yet remains hindered by common pathological barriers and sustained inflammation. Herein, we developed a top-down strategy to exfoliate short nanofibrils from Antheraea pernyi silk fibers featuring inherent Arg-Gly-Asp (RGD) motifs, followed by in situ growth of Au nanoparticles. The resulting platform (Au@ASFs) achieved superior spatial adaptability via catalytic oxygen propulsion, navigating across barriers to reach deep-seated lesions. Once localized, Au@ASFs provided phase-spanning multifunctional therapy through near-infrared (NIR)-triggered photothermal sterilization. Through RGD–integrin interactions, they also promoted hemostasis and M2 macrophage polarization to resolve persistent inflammation while enhancing fibroblast migration, angiogenesis, and neuronal differentiation. In vivo, Au@ASFs (+NIR) significantly improved closure of infected diabetic oral ulcers from 43.1 to 95.5% by day 7 and restored colon length in ulcerative colitis from 66.3 to 97.7% of healthy controls. In infected diabetic wounds, Au@ASFs (+NIR) increased closure from 63.8 to 89.1% by day 14. Transcriptomic analysis of wound tissues revealed reprogramming through suppressed NF-κB inflammatory signaling, activated Wnt5a/GSK-3β signaling for neuronal differentiation, and modulated PI3K-Akt signaling for tissue regeneration. Collectively, Au@ASF (+NIR) consistently resolves chronic epithelial diseases across disparate anatomical sites, establishing a unified drug-free paradigm that transcends site-specific constraints.