Prolonged blood circulation outperforms active targeting for nanocarriers-mediated enhanced hepatocellular carcinoma therapy in vivo.

Successful hepatocellular carcinoma (HCC) therapy in vivo remains a significant challenge due to the down-regulated expression of the receptors on the surface of tumor cells for compromised active targeting efficiency and cellular uptake of nanoparticles (NPs)-based drug delivery systems (DDSs) and "accelerated blood clearance" and premature unpackaging of NPs in vivo induced by the poly(ethylene glycol)ylation (PEGylation). Inspired by the repeatedly highlighted prolonged blood circulation property of RBCm-camouflaged NPs, we hypothesis that the prolonged blood circulation property resulting from RBCm coating outperforms the active targeting mechanisms of various targeting ligands for enhanced HCC therapy in vivo. Clarification of this hypothesis is therefore of great significance and urgency to break the afore mentioned bottlenecks that hamper the efficient HCC treatment in vivo. For this purpose, we reported in this study the first identification of a determining factor of nanocarriers for enhanced HCC therapy in vivo by the use of the previously fabricated pectin-doxorubicin nanoparticles (PDC-NPs) as a typical example, i.e., the natural RBCm was used as a stealth coating of PDC-NPs for the fabrication of biomimetic DDSs, PDC@RBC-NPs via hypotonic dialysis and mechanical co-extrusion methods. Comprehensive in vitro and in vivo evaluation and comparison of the properties and performance of PDC@RBC-NPs and PDC-NPs were performed in terms of colloidal stability, biosafety, drug release profiles, macrophage escape, anti-HCC effect. The resulting PDC@RBC-NPs outperformed PDC-NPs for HCC therapy in vitro and in vivo. Notably, PDC@RBC-NPs-treated BALB/c nude mice showed a significantly smaller final average tumor volume of 613 mm3 after 16 days than the PDC-NPs-treated group with an average value of 957 mm3. Therefore, the PDC@RBC-NPs developed herein showed great potential for clinical transformations due to the facile preparation and superior therapeutic efficiency against HCC. Most importantly, prolonged blood circulation was identified as a determining factor of nanocarriers instead of active targeting for enhanced HCC therapy in vivo, which could be used to direct the future design and development of advanced DDSs with greater therapeutic efficiency for HCC.

Polymeric coating lubricates nanocontainers to escape macrophage uptake for bioreceptor recognition.

Accurate drug delivery to the lesion has been deliberated for several decades, but one important phenomenon is usually neglected that the immune system can prevent smooth transportation of nanomedicine. Although injection would reduce first-pass effect, macrophages in the blood can still recognize and phagocytose nanomedicine. Here we show that a lubricated nanocontainer, which is prepared based on polyelectrolytes and mesoporous silica nanoparticles, can accurately target muscarinic bioreceptor while escaping from the identification of macrophages. Through in vitro and in vivo studies, this nanocontainer, combining both immune escape and bioreceptor targeting, has greatly improved the drug bioavailability. Additionally, this nanocontainer shows good biocompatibility, and the targeted heart tissues and other important metabolic organs, such as liver and kidney, keep physiological structures and functions without the detection of side effects. Furthermore, the mechanism of immune escape for the developed nanocontainer has been investigated by lubrication test and molecular simulation. We anticipate that our study will establish a new perspective on the achievement of immune escape-based targeted drug delivery, which can provide a fundamental approach for the design of related biomaterials.