The research suggests that the combination therapy system of EPTNs and HPTNs could be a new direction for liver cancer therapy.

Apoptotic vesicles (ApoVs) hold great promise for inflammatory regulation and tissue repair. However, little effort has been dedicated to developing ApoV-based drug delivery platforms, while the insufficient targeting capability of ApoVs also limits their clinical applications. This work presents a platform architecture that integrates apoptosis induction, drug loading, and functionalized proteome regulation, followed by targeting modification, enabling the creation of an apoptotic vesicle delivery system to treat ischemic stroke. Briefly, α-mangostin (α-M) was utilized to induce mesenchymal stem cell (MSC) apoptosis while being loaded onto MSC-derived ApoVs as an anti-oxidant and anti-inflammatory agent for cerebral ischemia/​reperfusion injury. Matrix metalloproteinase activatable cell-penetrating peptide (MAP), a microenvironment-responsive targeting peptide, was modified on the surface of ApoVs to obtain the MAP-functionalized α-M-loaded ApoVs. Such engineered ApoVs targeted the injured ischemic brain after systemic injection and achieved an enhanced neuroprotective activity due to the synergistic effect of ApoVs and α-M. The internal protein payloads of ApoVs, upon α-M activation, were found engaged in regulating immunological response, angiogenesis, and cell proliferation, all of which contributed to the therapeutic effects of ApoVs. The findings provide a universal framework for creating ApoV-based therapeutic drug delivery systems for the amelioration of inflammatory diseases and demonstrate the potential of MSC-derived ApoVs to treat neural injury.

No abstract

Oleanolic acid (3β-hydroxyolean-12-en-28-oic acid, OA) is a kind of pentacyclic triterpene, which widely distributes in nature. OA possesses a powerful anti-cancer effect; however, its low solubility limits its bioavailability and application. In this study, a new OA derivative, K73-03, was used to determine its effect on liver cancer cells and detailed molecular mechanisms. We found that K73-03 could significantly inhibit the cell viability, migration and colony formation of SMMC-7721 and HepG2 cells in a dose-dependent manner, having a stronger effect on HepG2 cells. Excess ROS was produced when treated with K73-03 compared with the control group. After adding a reactive oxygen scavenger, N-acetyl-L-cysteine (NAC), the expression of ROS was downregulated. For mitochondrial dysfunction, K73-03 could reduce Mitochondrial membrane potential (∆Ψm) and inhibit cell respiration. In mechanism studies, the ratio of Bax/Bcl-2 and the expressions of cleaved-caspase9 and cleaved-caspase3 in HepG2 cells were upregulated after K73-03 treatment, while the ratio of LC3B-II/I and the expression of Beclin1 were also increased. The protein expressions of p-JAK2, p-STAT3, COX-2, p65 and p-65 in K73-03 treated HepG2 cells were downregulated and the nuclear translocation of p65 was inhibited. In our study, K73-03 may lead to the disorder of mitochondria in HepG2 cells, leading to excessive ROS production and apoptosis in cells. Meanwhile, K73-03 could induce cell apoptosis by inhibiting JAK2/STAT3 pathway and NF-κB/P65 pathway.