Resistance to gemcitabine in pancreatic cancer poses a significant clinical challenge. Further investigation is warranted to assess whether nano-formulation strategy can be employed to enhance the sensitivity of resistant strains to gemcitabine therapy. In this study, using gemcitabine-resistant pancreatic cancer cell lines, we examined the therapeutic potential of a gemcitabine nanodelivery platform and assessed the ability to overcome drug resistance against resistant strains. Silencing of human equilibrative nucleoside transporter 1 (hENT1) led to reduced cellular uptake of gemcitabine, resulting in chemoresistance in pancreatic cancer. Gemcitabine nanoparticles circumvented the entry blockade caused by hENT1 silencing through endocytosis. Nanoparticle entry via clathrin-mediated endocytosis increased intracellular gemcitabine accumulation in gemcitabine-resistant pancreatic cancer cells. Moreover, gemcitabine nanoparticles are preferential in vivo delivery to tumor tissues, likely due to the enhanced permeability and retention effect. In comparison to free gemcitabine, gemcitabine nanoparticles demonstrate a more pronounced cytotoxic effect on gemcitabine-resistant pancreatic cancer cells, with favorable biosafety. This study improved the efficacy of gemcitabine through nanotechnology, providing a novel strategy to address gemcitabine-resistant pancreatic cancer.

Interactions of hepatic macrophages with local inflammatory microenvironment is the key factor promoting the development of acute liver failure (ALF). Hence, reprogramming pro-inflammatory M1 into anti-inflammatory M2 phenotype may offer a promising strategy for treating ALF by targeting inflammation. Our group found Carvedilol possessed potential anti-inflammatory property previously, which had been scarcely reported in ALF. We present a synergy strategy to induce macrophages into the phenotype M2-type anti-inflammatory macrophages with interleukin-4 (IL-4) and IL-10 at first. Then Carvedilol is loaded on the macrophage membrane-camouflaged biomimetic nano-platform (termed as M2M@CNP) to evade reticuloendothelial system (RES) and afford Carvedilol delivery to the inflammatory environment with overproduced reactive oxygen species (ROS), further prolonging its circulation and accumulation. Sustainably released Carvedilol produced anti-inflammatory, antioxidant and anti-apoptosis effects, combining local M2-type cell membranes (M2-CM) inhibited pro-inflammatory cytokines and ROS levels, which in turn promoted and amplified M1 to M2 phenotype polarization efficiency. This study offers new insights into the rational design of biomimetic nanosystems for safe and effective ALF therapy to accelerate the clinical translation.

Aging is a contributor to liver disease. Hence, the concept of liver aging has become prominent and has attracted considerable interest, but its underlying mechanism remains poorly understood. In our study, the internal mechanism of liver aging was explored via multi-omics analysis and molecular experiments to support future targeted therapy. An aged rat liver model was established with d-galactose, and two other senescent hepatocyte models were established by treating HepG2 cells with d-galactose and H₂O₂. We then performed transcriptomic and metabolomic assays of the aged liver model and transcriptome analyses of the senescent hepatocyte models. In livers, genes related to peroxisomes, fatty acid elongation, and fatty acid degradation exhibited down-regulated expression with aging, and the hepatokine Fgf21 expression was positively correlated with the down-regulation of these genes. In senescent hepatocytes, similar to the results found in aged livers, FGF21 expression was also decreased. Moreover, the expressions of cell cycle-related genes were significantly down-regulated, and the down-regulated gene E2F8 was the key cell cycle-regulating transcription factor. We then validated that FGF21 overexpression can protect against liver aging and that FGF21 can attenuate the declines in the antioxidant and regenerative capacities in the aging liver. We successfully validated the results from cellular and animal experiments using human liver and blood samples. Our study indicated that FGF21 is an important target for inhibiting liver aging and suggested that pharmacological prevention of the reduction in FGF21 expression due to aging may be used to treat liver aging-related diseases.

Liver transplantation (LT), an ultimate and vital method for treating end-stage liver disease, is often accompanied by ischemia-reperfusion injury (IRI) resulting from warm or cold ischemia of the donor liver. Organ protection techniques are used to improve the quality of liver grafts (from retrieval to implantation). Reactive oxygen species (ROS) cause oxidative stress, which is considered a crucial factor in IRI after LT. Nano antioxidants capable of scavenging ROS alleviate IRI in multiple types of organs and tissues. In this study, we synthesized ceria nanoparticles (NPs) with antioxidant properties using a pyrolysis method and covered them with phospholipid-polyethylene glycol to improve their biocompatibility in vivo. We investigated the potential organ-protective effect of ceria NPs and the underlying mechanisms. Ceria NPs promoted liver function recovery after LT by attenuating IRI in liver grafts in vivo. The protective effect of ceria NPs on liver grafts was investigated by applying hypothermic oxygenated machine perfusion ex vivo. Ceria NPs attenuated hypoxia reoxygenation- or H₂O₂-induced hepatocyte injury by enhancing mitochondrial activity and ROS scavenging in vitro. These effects may be associated with the activation of the nuclear factor erythroid-derived 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)/heme oxygenase 1 (HO-1) signaling pathway. In conclusion, ceria NPs may serve as a promising antioxidant agent for the treatment of hepatic IRI after LT.