Bioactive Decellularized Extracellular Matrix Platform Integrating Multifunctional Nanozymes and Cell-Laden Microgels for Acute Liver Failure Treatment

Mesenchymal stem cell (MSC) therapy has emerged as a promising alternative approach for treating acute liver failure (ALF) while confronting the shortage of low efficiency and poor engraftment within a hostile liver milieu. In this study, we establish a bioactive decellularized extracellular matrix (dECM) platform that incorporates dihydrolipoic acid (DHLA)-protected Pt nanoclusters doped with Cu (PtCu-DHLA) nanozymes and cell-laden microgels. The PtCu-DHLA nanozymes, selected for their versatility, function as antioxidant, anti-inflammatory, pro-proliferative, and pro-angiogenic agents, enhancing ALF alleviation and providing an optimal microenvironment for MSC transplantation. Additionally, a methacrylic anhydride (MA)-modified porcine liver-derived decellularized extracellular matrix (PLdECM) hydrogel (PLdECMMA) has been developed for the construction of microgels via microfluidic devices. Interferon γ (IFNγ) preconditioned MSCs encapsulated in PLdECMMA microgels exhibit enhanced immunomodulating activity and prolonged survival. PtCu-DHLA nanozymes and cell-laden microgels are codelivered by leveraging the PLdECM hydrogel for orthotopic transplantation. The transplanted dECM platform enables an efficient and successful rescue of CCl₄-induced ALF by counteracting oxidative stress, suppressing inflammatory storms, and promoting cellular regeneration. Overall, this study highlights a synergistic and reinforced strategy that combines biomimetic nanozymes with MSC therapy, offering significant potential for ALF treatment and broader applications in regenerative medicine.