Coordinated Two-Node Blockade of NF-κB and TGF-β/Smad Signaling Attenuates the Foreign Body Response to Prevent Capsular Contracture.

Background

Capsular contracture is driven by self-amplifying foreign body response (FBR) where inflammatory and fibrotic signals from fibroblasts and macrophages reinforce each other. We hypothesized that cogradient simultaneous blockade of NF-κB as an inflammatory node and TGF-β/Smad as fibrotic node could attenuate the FBR. Emodin has dual inhibitory activity but suffers from poor delivery.

Methods

Emodin liposomes (Emo-Lip) were characterized and tested on TGF-β1-stimulated NIH/3T3 fibroblasts and LPS-stimulated RAW264.7 macrophages. In a rat silicone implant model, periprosthetic injections were given for four weeks. Fibrous capsule formation was evaluated by histology, immunofluorescence, and FAPI-PET/CT. Transcriptomic analyses were performed to verify and predict relevant pathways.

Results

Emo-Lip had uniform size and high encapsulation efficiency. In vitro, Emo-Lip inhibited fibroblast migration, ROS production, myofibroblast differentiation (α-SMA+) as well as Ctgf expression, while suppressing M1 polarization and reduced IL-12/IL-6 secretion in macrophages. In vivo, Emo-Lip reduced capsule thickness, collagen area, and α-SMA/Col I expression, comparable to dexamethasone. Transcriptomics showed coordinated downregulation of inflammatory/fibrotic genes, and Western blot confirmed suppressed phosphorylation of Smad3.

Conclusions

Coordinated two-node blockade of NF-κB and TGF-β/Smad by liposomal emodin reprograms the FBR and effectively prevents capsular contracture in rats, offering a translational strategy for implant-associated fibrosis.