Efficient and Targeted siRNA Delivery to M2 Macrophages by Smart Polymer Blends for M1 Macrophage Repolarization as a Promising Strategy for Future Cancer Treatment.

Cancer remains an issue on a global scale. It is estimated that nearly 10 million people succumbed to cancer worldwide in 2020. New treatment options are urgently needed. A promising approach is a conversion of tumor-promoting M2 tumor-associated macrophages (TAMs) as part of the tumor microenvironment to tumor-suppressive M1 TAMs by small interfering RNA (siRNA). In this work, we present a well-characterized polymeric nanocarrier system capable of targeting M2 TAMs by a ligand-receptor interaction. Therefore, we developed a blended PEI-based polymeric nanoparticle system conjugated with mannose, which is internalized after interaction with macrophage mannose receptors (MMRs), showing low cytotoxicity and negligible IL-6 activation. The PEI-PCL-PEI (5 kDa-5 kDa-5 kDa) and Man-PEG-PCL (2 kDa-2 kDa) blended siRNA delivery system was optimized for maximum targeting capability and efficient endosomal escape by evaluation of different polymer and N/P ratios. The nanoparticles were formulated by surface acoustic wave-assisted microfluidics, achieving a size of ∼80 nm and a zeta potential of approximately +10 mV. Special attention was given to the endosomal escape as the so-called bottleneck of RNA drug delivery. To estimate the endosomal escape capability of the nanocarrier system, we developed a prediction method by evaluating the particle stability via the inflection temperature. Our predictions were then verified in an in vitro setting by applying confocal microscopy. For cellular experiments, however, human THP-1 cells were polarized to M2 macrophages by cytokine treatment and validated through MMR expression. To show the efficiency of the nanoparticle system, GAPDH and IκBα knockdown was performed in the presence or absence of an MMR blocking excess of mannan. Cellular uptake, GAPDH knockdown, and NF-κB western blot confirmed efficient mannose targeting. Herein, we presented a well-characterized nanoparticle delivery system and a promising approach for targeting M2 macrophages by a mannose-MMR interaction.

Synthesis and Application of Low Molecular Weight PEI-Based Copolymers for siRNA Delivery with Smart Polymer Blends.

Polyethylenimine (PEI) is a commonly used cationic polymer for small-interfering RNA (siRNA) delivery due to its high transfection efficiency at low commercial cost. However, high molecular weight PEI is cytotoxic and thus, its practical application is limited. In this study, different formulations of low molecular weight PEI (LMW-PEI) based copolymers polyethylenimine-g-polycaprolactone (PEI-PCL) (800 Da-40 kDa) and PEI-PCL-PEI (5-5-5 kDa) blended with or without polyethylene glycol-b-polycaprolactone (PEG-PCL) (5 kDa-4 kDa) are investigated to prepare nanoparticles via nanoprecipitation using a solvent displacement method with sizes ≈100 nm. PEG-PCL can stabilize the nanoparticles, improve their biocompatibility, and extend their circulation time in vivo. The nanoparticles composed of PEI-PCL-PEI and PEG-PCL show higher siRNA encapsulation efficiency than PEI-PCL/PEG-PCL based nanoparticles at low N/P ratios, higher cellular uptake, and a gene silencing efficiency of ≈40% as a result of the higher molecular weight PEI blocks. These results suggest that the PEI-PCL-PEI/PEG-PCL nanoparticle system could be a promising vehicle for siRNA delivery at minimal synthetic effort.

A Health Crisis in the Age of Misinformation: How Social Media and Mass Media Influenced Misperceptions about COVID-19 and Compliance Behavior.

The media are important information disseminators in society. Particularly in uncertain times, such as the COVID-19 pandemic, citizens are very "media dependent." The way in which people are informed about the coronavirus heavily depends on the type of media they use. Especially on social media, the share of misinformation is considerable, which might impact the way in which people comply with preventive measures. Our study investigates how media use affects misperceptions about the coronavirus and whether this influences important behavioral determinants as well as compliance behavior itself. The results of a unique 5-wave panel survey (N = 1,741) conducted between April 2020 and October 2020 show that the use of mass media reduces misperceptions. The same was found for Twitter users, whereas Facebook and Instagram users have more misperceptions about the coronavirus. Misperceptions negatively influence the perceived severity, susceptibility and efficacy of preventive measures taken by governments, which may ultimately result in decreased compliance. Our findings underline the important role of media consumption and misperceptions in shaping citizens' beliefs and behavior regarding COVID-19. They re-emphasize the importance of mass media, such as newspapers, television broadcasts or reliable news websites, to inform the public about current affairs. They also imply that platform media might be more heterogeneous in their effects than mass media.