Antiviral nanomedicine: Advantages, mechanisms and advanced therapies

Abstract

The emergence of novel viral pathogens and the limitations of conventional antiviral therapies necessitate innovative strategies to combat persistent and pandemic threats. This review details the role of viral infections and antiviral nanomedicines, delving into the mechanisms of action and antiviral advantages of nanomedicines, as well as the latest research advances in this field. The review systematically categorizes the mechanisms of antiviral nanodrugs into a framework that integrates previously fragmented knowledge, and innovatively summarizes the unique attributes and advantages of antiviral nanodrugs compared to small-molecule drugs. Nanotherapies are proposed in this review to conclude advanced nanoantivirals (e.g., light-activated nanophotosensitizers, biomimetic decoys, PROTAC-based degraders, and gene-silencing platforms) and offer a distinctive narrative perspective, with the aim of presenting a merged and integrated overview of nanodrugs. By intuitively highlighting their commonalities in mechanisms or similarities in application methods, readers may better appreciate the innovative characteristics of different antivirals. We further discuss translational challenges and propose interdisciplinary solutions and future directions to accelerate the development of next-generation antiviral strategies. This review aims to inspire transformative research at the nexus of virology, nanotechnology, and precision medicine.

Keywords: Antiviral nanomedicine; Biomimetic nanomaterials; Nanotechnology; Targeted drug delivery; Virus-host interaction.

Graphical abstract

Fig. 1

a) Schematic diagram of the structures of several prevalent enveloped/non-enveloped viruses b) Classification based on whether the virus has an envelope and the Baltimore Classification System. Created in https://BioRender.com.

Fig. 2

Schematic diagram of the infection lifecycle of SARS-CoV-2 as the representative virus. Created in https://BioRender.com.

Fig. 3

Schematic of possible action mechanisms of antiviral nanodrugs. Nanodrugs can i) directly destroy/inactivate viruses, ii) inhibit virus–cell interaction to inhibit viral infection, iii) disrupt viral proliferation and viral life cycle, iv) assist in treating viral infections. Created in https://BioRender.com.

Fig. 4

Limitations of conventional antiviral drugs and unique attributes and advantages of nanodrugs. Created in https://BioRender.com.

Fig. 5

Schematic representation of milestones of antiviral nanodrugs[81,[121], [122], [123],[128], [129], [130]]. Reproduced with permission [123]. Copyright 2017, Elsevier. Reproduced with permission [122]. Copyright 2020, National Academy of Sciences. Reproduced with permission [130]. Copyright 2022, Springer Nature. Reproduced with permission [128]. Copyright 2022, Wiley-VCH. Reproduced with permission [129]. Copyright 2024, Springer Nature.

Fig. 6

Schematic diagram of antiviral nanodrugs in light nanotherapy.

Fig. 7

a) Photosensitizing molecules that exhibit antiviral activity under visible and/or infrared wavelengths in antiviral phototherapy. Reproduced with permission [164]. Copyright 2022, MDPI. b) Schematic illustration of the GO and virus interaction. Reproduced with permission [165]. Copyright 2014, WILEY‐VCH. c) Schematic illustration of the working principle of Cu_xO/TiO2 photocatalyst in antiviral therapy. d) The Cu_xO/TiO2-coated sheet produced a robust inactivation of bacteriophage Qβ in comparison to the control sheet without the photocatalyst. Reproduced with permission [157]. Copyright 2020, MDPI. e) Schematic drawing of UCN structure and mechanism of action of UCN-based PDT; f) Kaplan–Meier survival curve of BALB/c mice that were inoculated with photodynamically inactivated DENV2, showing the possibility to eradicate Dengue virus pathogenesis in BALB/c mice through ZnPc-UCNPs phototherapy. Reproduced with permission [162]. Copyright 2011, Elsevier.

Fig. 8

Schematic diagram of antiviral nanodrugs in targeted-rupture nanotherapy. Created in https://BioRender.com.

Fig. 9

a) After co-incubation of GPS_6.8 with VSV, disruption of the viral envelope was observed under TEM. Scale bars:100 nm. b) GPS_6.8 selectively interacts with AMLM, causing rupture of its lipid membrane. Scale bars: 100 nm; (Red arrows indicate MLM or AMLM, while the blue arrows indicate GPS_6.8) c). Titers of SARS-CoV-2 in NHBE cells infected with 10 MOI SARSCoV-2 in the presence or absence of GPS_6.8 for 18 h were determined by qRT-PCR analysis. d) Flow cytometry analysis of HeLa cells infected with VSV-GFP (0.01 MOI) or indicated titers of ADV-mNeonGreen, and treated with GPS_6.8 in the meantime. e) Survival rates were higher when treated with GPS_6.8. Reproduced with permission [109]. Copyright 2022, Wiley‐VCH. f) Schematic illustration of LEAD strategy and development of antiviral brain-penetrating nanopeptides AH-D that inhibited Zika virus in an in vivo mouse model. Reproduced with permission [167]. Copyright 2018, Springer Nature.

Fig. 10

a) Schematic diagram of antiviral nanodrugs in Biomimetic nanotherapy. b) Sulfonate-functionalized inorganic nanoparticles that mimic HSPG inhibit viral binding to the cellular surface HSPG receptor while acting as a virus destroyer. Reproduced with permission [187]. Copyright 2017, Springer Nature. c) Blockage of viral entry and infection through virus-nanosponge binding. d) Cellular nanosponges Epithelial-NS (made from lung epithelial type II cells) and MΦ-NS (made from macrophage membranes) highly neutralize SARS-CoV-2 infectivity, compared with nanosponges made from red blood cell membranes (RBC-NS, used as a control). Reproduced with permission [192]. Copyright 2020, American Chemical Society. Schematic representation of the preparation and mechanism of action of nanodecoys. e) Schematic illustration of the inhaled ACE2-engineered microfluidic microsphere for neutralization of COVID-19 and cytokines. f) Immunofluorescence staining of paraffin sections of mouse lung for pseudotyped SARS-CoV-2-EGFP (green) and DAPI (blue) in healthy, control, PMS, and iAE-PMS groups. Scale bar, 100 μm. g) Inhaled ACE2-engineered porous microsphere inhibited cytokine storm factors. Reproduced with permission [90]. Copyright 2021, Elsevier.

Fig. 11

a) Mechanism of action of antiviral PROTACs in degrading viral proteins. Reproduced with permission [225]. Copyright 2024, Elsevier. b) Schematic illustration of the generation of PROTAC viruses and the sequences of amino acids and genes of PTD. c) Viral titers in mouse tissues at day 3 after infection with 10⁵ PFU of WT WSN or PROTAC viruses. d) and e) Survival rates and body weights of mice after intranasal infection with the indicated viruses. Reproduced with permission [224]. Copyright 2022, Springer Nature.

Fig. 12

a) Schematic diagram of nanocarrier delivery of antiviral siRNA. Created in https://BioRender.com. b) Delivery of candidate siRNA against SARS-CoV-2 via LNPs. Reproduced with permission [237]. Copyright 2021, Elsevier. c) Mechanism of the action of shDNA-Gal-AMSN complex into HCV-infected cells. d) Biodistribution studies by whole body imaging. e) Antiviral effect of shDNA-Gal-AMSN complex on HCV RNA levels. Reproduced with permission [250]. Copyright 2020, American Chemical Society. f) Schematic representation describing the design and function of the nanozyme with DNA oligonucleotides complementary to the sequence at the HCV RNA position. Reproduced with permission [252]. Copyright 2012, National Academy of Sciences of the United States of America.

Fig. 13

a) Schematic diagram of inhalable IFNλ-PSNP and b) confocal fluorescence images of alveolar region of the lungs 1 day and 3 days after IFNλ-PSNP inhalation: nucleus (blue, Hoechst), IFNλ (red). Reproduced with permission [258]. Copyright 2024, American Chemical Society. c) Schematic illustration of inhalable nanoDEX and the two-step strategy against COVID-19 cytokine storm: cytokine down-regulation by DEX and cytokine neutralization by the iSEND. d,e) nanoDEX reduced cytokine levels, significantly suppressed the LPS-induced severe lung injury characterized by alveolar cavity disappearance, alveolar wall incrassation, inflammatory cell infiltration, and vascular dilatation and congestionin an acute pneumonia mouse model. Reproduced with permission [269]. Copyright 2023, American Association for the Advancement of Science.