Quercetin-Loaded Nanoparticle-Modified Decellularized Tissue-Engineered Vascular Graft Regulates Macrophage Polarization and Promotes In Vivo Graft Remodeling

Tun Wang,1,2,* Zhenyu He,1,2,* Peng Lu,1,2 Sheng Liao,1,2 Siyuan Cheng,1,2 Tianjian Wang,1,2 Yangyang An,1,2 Zibo Cheng,1,2 Chang Shu1– 3 1Department of Vascular Surgery, the second Xiangya Hospital, Central South University, Changsha, 410011, People’s Republic of China; 2Institute of Vascular Diseases, Central South University, Changsha, 410011, People’s Republic of China; 3Center of Vascular Surgery, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chang Shu, Email [email protected]: Arteriovenous graft (AVG) is an important option for establishing hemodialysis access in patients with end-stage chronic kidney disease (CKD). Decellularized tissue-engineered vascular graft (dTEVG), due to its excellent biocompatibility and regenerative potential, holds promise for use in AVG; however, poor remodeling remains a challenge. Quercetin (Qu) can effectively regulate macrophage polarization and promote tissue remodeling and regeneration, yet its low bioavailability limits its clinical application.Methods: Here, we developed a nano-localized drug delivery system using Qu-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (Qu@PNPs), prepared via a nanoprecipitation method and subsequently modified onto the surface of dTEVG. In vitro and in vivo experiments were performed to assess the biocompatibility of Qu@PNPs and their effect on macrophage polarization. Additionally, the impact of Qu@PNPs modification on dTEVG remodeling was evaluated in both subcutaneous and AVG rat models.Results: Our study results demonstrated that Qu@PNPs exhibited good biocompatibility and achieved sustained drug release on dTEVG. Furthermore, these drug-loaded nanoparticles inhibited M1 macrophage polarization while promoting M2 polarization, significantly improving the in vivo remodeling of dTEVG, as evidenced by increased early recellularization and peripheral neovascularization.Conclusion: Together, the development of the nano-localized drug delivery system effectively enhanced the application of Qu, providing experimental evidence for its use in dTEVG. Additionally, it offers new strategies and approaches for optimizing dTEVG design and clinical translation.Keywords: arteriovenous graft, decellularized tissue-engineered vascular graft, macrophage polarization, nanoparticles, quercetin, graft remodeling