The severe global shortage of donor organs necessitates the utilization of aged extended-criteria donor (ECD) livers, which are susceptible to ischemic injury and exhibit a sluggish regeneration due to hepatic senescence. While mesenchymal stem cell-derived exosomes show regenerative promise, clinical translation is hindered by manufacturing bottlenecks and batch heterogeneity. In this study, we have developed a highly controllable, microfluidic-engineered exosome-mimetic lipid nanotherapeutic (LMP) to rejuvenate aged livers. The proposed procedure employs a "decoding and synthetic reconstruction" paradigm, where the regenerative cargo of natural exosomes is converted to a standardized 10-component core, comprising three master-regulatory miRNAs and seven functional proteins. In vitro and in vivo evaluations have demonstrated that the LMP exhibits the requisite biosafety, rapid hepatic internalization, and immunological inertness. A systemic administration of LMP effectively revitalizes baseline liver function in aged mice. In terms of mechanism, the multidimensional rejuvenation is driven by a modulating of the collapsed mitochondrial energy networks, attenuating the senescence-associated secretory phenotype (SASP), and reducing age-related fibrotic architectures. The LMP actively remodels the hepatic immune microenvironment by promoting a shift in the relative distribution of macrophage populations toward a pro-resolving M2-like phenotype, significantly attenuating chronic inflammaging. This study presents a highly scalable, multi-pathway nanomedicine that can successfully reset the hepatic senescent network, providing a promising preclinical pharmacological strategy that warrants future testing in rigorous donor-graft and transplantation settings to fully evaluate its clinical translational potential.
