Multi-omics-guided targeting of the CD14-NF-κB axis with PGA1-loaded liposomes restores CD14^hi TSPCs function and...

Type 2 diabetes mellitus (T2DM) is common in patients with rotator cuff tears (RCTs) and is associated with poor tendon-bone healing and high retear rates. Tendon stem/progenitor cells (TSPCs) are central to tendon-bone integration, but how T2DM reprograms TSPCs and whether this can be reversed remain unclear.

T2DM was induced in rodents, followed by tendon single-cell RNA sequencing, serum metabolomics and tendon proteomics. TSPCs were isolated for functional assays and analysis of underlying signaling. CD14-overexpressing (CD14^hi) TSPCs modeled diabetic-like dysfunction. Free PGA1 and Lipo@PGA1 were evaluated in vitro and in a diabetic RCT model, alongside liposome characterization and safety assessment.

Multi-omics analysis revealed that T2DM induced marked remodeling of the tendon-resident cell landscape, with TSPCs exhibiting upregulated CD14 expression and enrichment of NF-κB-related inflammatory and apoptotic pathways, alongside systemic depletion of serum PGA1. Diabetic and CD14^hi TSPCs showed reduced progenitor-like functional properties, accompanied by activation of the CD14-NF-κB axis. PGA1 supplementation or CD14 silencing attenuated NF-κB activation and restored TSPC stemness. PGA1-loaded liposomes showed favorable physicochemical properties, good local retention at the tendon-bone interface, and acceptable systemic and cellular biocompatibility. In the diabetic RCT model, Lipo@PGA1 significantly increased TSPCs, improved tendon-bone healing, and enhanced biomechanical properties and forelimb function.

T2DM reprograms tendon-resident TSPCs through a CD14-PGA1-NF-κB axis, driving apoptosis and reducing progenitor-like functional properties. Multi-omics-guided targeting of this axis with PGA1-loaded liposomes restores CD14^hi TSPCs function and enhances tendon-bone repair in diabetic RCT, supporting a mechanism-based therapeutic strategy.