The complement system is a key component of innate immunity implicated in the neutralization and clearance of invading pathogens. Dextran coated superparamagnetic iron oxide (SPIO) nanoparticle is a promising magnetic resonance imaging (MRI) contrast agent. However, dextran SPIO has been associated with significant number of complement-related side effects in patients and some agents have been discontinued from clinical use (e.g., Feridex™). In order to improve the safety of these materials, the mechanisms of complement activation by dextran-coated SPIO and the differences between mice and humans need to be fully understood. 20 kDa dextran coated SPIO nanoworms (SPIO NW) were synthesized using Molday precipitation procedure. In vitro measurements of C3 deposition on SPIO NW using sera genetically deficient for various components of the classical pathway (CP), lectin pathway (LP) or alternative pathway (AP) components were used to study mechanisms of mouse complement activation. In vitro measurements of fluid phase markers of complement activation C4d and Bb and the terminal pathway marker SC5b-C9 in normal and genetically deficient sera were used to study the mechanisms of human complement activation. Mouse data were analyzed by non-paired t-test, human data were analyzed by ANOVA followed by multiple comparisons with Student-Newman-Keuls test. In mouse sera, SPIO NW triggered the complement activation via the LP, whereas the AP contributes via the amplification loop. No involvement of the CP was observed. In human sera the LP together with the direct enhancement of the AP turnover was responsible for the complement activation. In two samples out of six healthy donors there was also a binding of anti-dextran antibodies and C1q, suggesting activation via the CP, but that did not affect the total level of C3 deposition on the particles. There were important differences and similarities in the complement activation by SPIO NW in mouse versus human sera. Understanding the mechanisms of immune recognition of nanoparticles in mouse and human systems has important preclinical and clinical implications and could help design more efficient and safe nano-formulations.

As exemplified by the COVID-19 pandemic, highly infectious respiratory viruses can spread rapidly in the population because of a lack of effective approaches to control viral replication and spread. Niclosamide is an old anthelminthic drug (see the essential medicine list of the World Health Organization) with pleiotropic pharmacological activities. Several recent publica-tions demonstrated that niclosamide has broad antiviral activities and potently inhibits viral rep-lication, including replication of SARS-CoV-2, SARS-CoV, and dengue viruses. Unfortunately, it is almost entirely insoluble in water, which limits its clinical use. We developed a cost-effective lipid nanoparticle formulation of niclosamide (nano-NCM) using only Food and Drug Admin-istration-approved excipient and demonstrated potency against SARS-CoV-2 infection in Vero E6 and ACE2-expressing lung epithelium cells in vitro.

Nanoparticles are recognized and cleared by Kupffer cells (KCs) in the liver. This process complicates the development of targeted nanoparticles because of significant reduction of number of nanoparticles that can reach target tissues. Macrophage scavenger receptor SR type AI/II is the central phagocytic receptor that has been shown to promote in vitro uptake of many nanoparticle types. In this paper, the authors set out to clarify the role of SR-AI/II in the in vivo liver clearance of 10kDa dextran superparamagnetic iron oxide (SPIO) Feridex-IV® and 20kDa dextran-coated SPIO nanoworms (SPIO NWs). Feridex showed efficient SR-AI/II-dependent uptake by isolated KCs in vitro, whereas SPIO NWs showed no uptake by KCs. Both Feridex and SPIO NWs showed a very short and nearly identical circulation half-life and efficient uptake by KCs in vivo. The SR-AI/II inhibitor, polyinosinic acid, prolonged the circulation half-life of both Feridex and SPIO NWs, but did not reduce the KC uptake. The circulation half-life and KC uptake of Feridex and SPIO NWs were identical in SR-AI/II-deficient mice and wild-type mice. These data suggest: (1) there is a limited correlation between in vitro and in vivo uptake mechanisms of nanoparticles in KCs; and (2) redundant, SR-AI/II independent mechanisms play a significant role in the nanoparticle recognition by KCs in vivo. Understanding the complexity of nanoparticle clearance assays and mechanisms is an important step to improving the design of “stealthy” nanoparticles.