Nanosponges: An overlooked promising strategy to combat SARS-CoV-2

Abstract

Among explored nanomaterials, nanosponge-based systems have exhibited inhibitory effects for the biological neutralization of, and antiviral delivery against, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). More studies could pave the path for clarification of their biological neutralization mechanisms as well as the assessment of their long-term biocompatibility and biosafety issues before clinical translational studies. In this review, we discuss recent advances pertaining to antiviral delivery and inhibitory effects of nanosponges against SARS-CoV-2, focusing on important challenges and opportunities. Finally, as promising approaches for recapitulating the complex structure of different organs/tissues of the body, we discuss the use of 3D in vitro models to investigate the mechanism of SARS-CoV-2 infection and to find therapeutic targets to better manage and eradicate coronavirus 2019 (COVID-19).

Keywords: Antiviral delivery; Biological neutralization; COVID-19; Nanosponges; SARS-CoV-2; Viral inactivation.

Nanosponges are promising candidates for antiviral drug delivery and biological neutralization.

Figure 1

Schematic of the structure of cyclodextrin-based nanosponges. Adapted, with permission, from .

Figure 2

Advantages and disadvantages of nanosponges in drug delivery applications.

Figure 3

(a) Cellular nanosponges engineered for inhibitory effects against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To express azido groups, the host cells were incubated with N-azidoacetylmannosamine-tetra-acylated (Ac4ManNAz). Then, the collected membranes were used to coat poly(lactic-co-glycolic acid) (PLGA) polymers to produce cellular nanosponges expressing azido groups (N₃-NS). Functionalization with heparin was performed by applying dibenzocyclooctyne groups (DBCO-heparin), which conjugated to azido-NS via copper-free click chemistry. The resulting heparin-modified cellular nanosponges (HP-NS) were examined for SARS-CoV-2 viral infectivity applications. (b) Dose-dependent binding of different HP-NS preparations with SARS-CoV-2 S proteins. (c) Dose-dependent viral infectivity inhibition by N₃-NS and various HP-NS formulations with low (L), medium (M), and high (H) heparin densities. Reproduced, with permission, from .

Figure 4

Membrane nanoparticles constructed from angiotensin-converting enzyme 2 (ACE2)-rich cells with inhibitory effects against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Figure 5

(a) Nanodecoys designed for neutralizing the S1 spike protein. S1 (red) and nanodecoys (white) interacted after their co-culture with lung cells (green). These nanodecoys were internalized by macrophages (confocal image; CD4, red). In addition, the nanodecoys were internalized by macrophages after co-culturing with lung cells (confocal image; CD90, green). Scale bars: 50 μm. (b) SARS-CoV-2-mimicking viruses were neutralized using the designed nanodecoys. Scale bars: 100 nm. (c) Inhalation of nanodecoys in a mouse model: these nanodecoys directly accumulated in the lung, which is one of the main targets of SARS-CoV-2 replication/infection. (d) The inhalation of nanodecoys enhanced clearance of the SARS-CoV-2 mimic in a mouse model. Reproduced, with permission, from .

Figure 6

(a) Functionalized liposomal-based nanotrappers utilizing anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-neutralizing antibodies, phagocytosis-specific phosphatidylserines, or recombinant angiotensin-converting enzyme 2 (ACE2). The accumulation and trapping of SARS-CoV-2 virions was achieved by these nanotrappers in the lung, producing virus–nanotrap complexes. (b) Pseudo-colored scanning electron microscopy (SEM) images of nanotrap complexes with SARS-CoV-2 pseudovirus. (c) (i) Untreated (right upper lobe), virus alone (right middle lobe), and virus–nanotrap complexes (lingula) regions in a human ex vivo lung perfusion system. (ii) Luciferase expression quantification analyses, 8 h after infection. (iii) Ex vivo lung perfusion after hemoxylin and eosin (H&E) staining, including untreated, virus alone, and virus–nanotrap complex samples. Reproduced, with permission, from .

Figure 7

Development of nanosponge-laden 3D in vitro models to manage severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and replication. (a) Once produced, nanosponges active against SARS-CoV-2 infection can be loaded into various 3D in vitro models, including hydrogels, organoids, spheroids, 3D bioprinted constructs, nanofibrous scaffolds, microfluidic-on-chips, and so on. The developed 3D model can be then used against SARS-CoV-2 infection for different applications, such as: discovery of novel and effective drugs to treat COVID-19; to study the development of different diseases in the presence of SARS-CoV-2, and the inhibitory roles of nanosponges in these developmental stages; to study the mechanism of infection and inhibition in the presence of nanosponges; to investigate host–virus complex interactions; and for disease modeling of (b) different tissues/organs that can be severely affected by SARS-CoV-2.