Summary and Perspectives
The recent history has shown the spread of different viral pandemics such as H1N1 flu, HIV, and SARS. Nowadays, the SARS-Cov-2 pandemic global lockdown has profoundly changed the daily life of most humans, causing uncertainty in short and middle time perspectives. In this context, the scientific community has responded to protect the population by studying new vaccines and disinfection methods to be applied in the near future. Despite this tough work, a SARS-Cov-2 vaccination will hopefully be available in 1–2 years, making this epidemic transient period gloomy with increased instability. The study of more effective vaccines and the production of a wide range antiviral agents is nowadays an extremely hot topic.
HNMs comprise a family of materials that share a nanostructured hard core and a tunable surface chemistry. In this contribution, we have methodically reviewed different HNMs for antiviral properties. HNMs can have antiviral properties per se, blocking the viral replication and diffusion, or their antiviral properties can be tailored, playing with surface chemistry. HNMs can be used to block viral entry and arrest infection at the early stage. The mechanisms rely on different actions including breaking of capsid disulfide bonds (e.g., noble metal nanoparticles), capsid oxidation (e.g., CuONPs), mimicking of cell surface (e.g., carbon NMs), or mechanical disruption (e.g., AuNPs or graphene). Surface functionalization additionally confers a higher specificity and pharmacological activity toward the targeted virus. In particular, the high local concentration of ligands on functionalized HNM surface imparts a high multivalent effect, enhancing the viral trapping efficiency of NMs. Interestingly, HNMs that show an intrinsic antiviral activity can further enhance their antiviral efficacy via surface functionalization. Some antiviral HNMs are good photosensitizers (e.g., CuONPs) or exert photothermal activity (e.g., carbon NMs), thus their antiviral activity can be trigged by light stimulation. More importantly, most of the settled strategies target common viral entry mechanisms and can be adopted to fight a wide viral spectrum. HNMs have been also applied as antiviral agents by their interaction with host cells. HNMs are able to block viral replication machinery in host cells (e.g., CNTs and fullerenes), inhibiting endogenous enzyme activity. Additionally, HNMs can be explored for the delivery of antiviral molecules, showing a better antiviral activity and reducing side effects in vitro and in vivo. Some HNMs can also regulate the ROS homeostasis of host cells, reduce apoptosis, and enhance host cell survival during the infection. Finally, we have reviewed the role of HNMs on immunity. In particular, HNMs can stimulate the innate immune response, mainly inducing overexpression of interferon and cytokines. This effect can alert sentinel cells and generally warn the immune system of the infection. HNMs can be also used for the activation of the adaptive immune response, foreseeing vaccination. Due to the similar size of a virus, functionalized HNMs with antiviral molecules (virus-like particles) can enhance their immunogenicity.
Certainly a huge effort should be done for translation of the research into clinics. Indeed, HNM applications as antivirals are still in the early phase of research. Several challenges still need to be tackled before their safe use. At the current stage, some HNMs have been approved only for surface disinfection. For instance, CuNPs have been used in filters for the preparation of highly efficient broad spectrum antiviral masks.50 Some HNMs have been already clinically approved. For example, FeNPs were approved for imaging and as a drug to treat iron deficiency anemia in adult patients with chronic kidney disease, while AuNPs are in clinical trials for the treatment of prostate cancer (photothermal therapy).154,155 However, at the moment no clinical trials are running for the use of HNMs as antiviral agents. In fact, there are still several concerns on the applications of HNMs in drug formulations. Compared to molecules, where mainly concentration and exposure routes are concerned, solving HNM toxicity issues is much more complicated. Composition, size, shape, and surface functionalization must be considered to respond to the requirement for safety regulations. Additionally, interaction on HNMs with the immune system must be better elucidated. In particular, the activation of the immune system and complement activation-related pseudoallergy must be taken into account.156 For instance, ferumoxytol (a FeNP-based drug) has been reported to generate severe anaphylactic reactions in humans, 18 of which were fatal.156 This is due to the possible interaction of HNMs with mast cells, provoking their degranulation/activation and release of histamine even at the first exposure (pseudoallergic-mediated hypersensitivity). Besides, the mechanism of activation of these cells is still unknown, although it was found that it depends on the HNM composition, size, and surface chemistry and on the corona formation.156 On the other hand, it has been demonstrated that HNMs can travel to the draining lymph nodes, targeting resident dendritic cells and macrophages. Therefore, they are able to interact with antigen presenting cells to stimulate innate and adaptive immune responses.156 We believe that a joint venture of different chemists, materials scientists, virologists, toxicologists, and medical doctors can push forward the preparation and safe application of HNMs in this field, hoping to prevent and eventually block the rise of new viral pandemics.