Microfluidics-enabled Serial Assembly of Lipid-siRNA-sorafenib Nanoparticles for Synergetic Hepatocellular Carcinoma Therapy.

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 we present the microfluidics-enabled serial assembly (MESA) of mNPs. 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 benefits 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, our strategy is promising as a sorafenib/siRNA combination therapy and MESA can be a universal platform for fabricating complex nanosystems. This article is protected by copyright. All rights reserved.