Liver fibrosis is a common pathological response to chronic hepatic injury. STAT3 is actively involved in the fibrogenesis and angiogenesis seen in liver fibrosis. S3I-201 (NSC 74859) is a chemical inhibitor of STAT3 activity, which blocks the dimerization of STAT3, STAT3-DNA binding and transcription activity. This study evaluated the effects of S3I-201 against liver fibrosis. S3I-201 inhibited the proliferation, migration, and actin filament formation in primary human hepatic stellate cells (HSCs), as well as the expression of α-SMA, collagen I and TIMP1 in both primary HSC and in a CCl-induced fibrosis mouse model. S3I-201 induced both apoptosis and cell cycle arrest in the HSC cell line (LX-2). S3I-201 inhibited the expression of fibrogenesis factors TGFβ1 and TGFβRII, as well as the downstream phosphorylation of Smad2, Smad3, Akt and ERK induced by TGFβ1. In addition to fibrogenesis, both in vitro and in vivo assays showed that S3I-201 inhibited angiogenesis through expression suppression of VEGF and VEGFR2. Moreover, S3I-201 also had a synergistic effect with sorafenib, an FDA approved liver cancer drug, in the proliferation, apoptosis, angiogenesis and fibrogenesis of HSC. S3I-201 suppressed liver fibrosis through multiple mechanisms, and combined with sorafenib, S3I-201 could be a potentially effective antifibrotic agent.

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Multi‐component nanoparticles (mNPs) hold great potential for disease prevention and treatment. However, a major barrier is the lack of versatile platforms to accommodate steps of assembly processes of mNPs. Here the microfluidics‐enabled serial assembly (MESA) of mNPs is presented. The microfluidic chip, as a mini‐conveyor of initial materials, sequentially enables the assembly of sorafenib supramolecule, electrostatic adsorption of siRNA, and surface assembly of protective lipids. The produced lipid‐siRNA‐sorafenib nanoparticles (LSS NPs) have ultrahigh encapsulation efficiencies for sorafenib (≈100%) and siRNA (≈95%), which benefit from the accommodation of both fast and slow processes on the chip. Although carrying negative charges, LSS NPs enable cytosolic delivery of agents and high gene silencing efficiency within tumor cells. In vivo, the LSS NPs delivering hypoxia‐induced factor (HIF1α)‐targeted siRNA efficiently regress tumors of Hep3B xenograft and hepatocellular carcinoma patient‐derived primary cells xenograft (PDCX) and finally extend the average survival of PDCX mice to 68 days. Thus, this strategy is promising as a sorafenib/siRNA combination therapy, and MESA can be a universal platform for fabricating complex nanosystems.

Antivirals that can combat coronaviruses, including SARS‐CoV‐2 and associated mutants, are urgently needed but lacking. Simultaneously targeting the viral physical structure and replication cycle can endow antivirals with sustainable and broad‐spectrum anti‐coronavirus efficacy, which is difficult to achieve using a single small‐molecule antiviral. Thus, a library of nanomaterials on GX_P2V, a SARS‐CoV‐2‐like coronavirus of pangolin origin, is screened and a surface‐functionalized gold nanocluster (TMA‐GNC) is identified as the top hit. TMA‐GNC inhibits transcription‐ and replication‐competent SARS‐CoV‐2 virus‐like particles and all tested pseudoviruses of SARS‐CoV‐2 variants. TMA‐GNC prevents viral dissemination through destroying membrane integrity physically to enable a virucidal effect, interfering with viral replication by inactivating 3CL protease and priming the innate immune system against coronavirus infection. TMA‐GNC exhibits biocompatibility and significantly reduces viral titers, inflammation, and pathological injury in lungs and tracheas of GX_P2V‐infected hamsters. TMA‐GNC may have a role in controlling the COVID‐19 pandemic and inhibiting future emerging coronaviruses or variants.