A series of pathogenic viruses, represented by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), pose significant threats to human health and socioeconomic stability, highlighting the urgent need for effective antiviral strategies to address these pressing public health concerns. In the field of antiviral therapy, antivirals that exert rapid inhibition and vaccines that provide long-term prevention are both of paramount importance for the intervening against fatal viral infections. It will be highly desirable to integrate the two strategies into a single antiviral agent, achieving synergistic therapeutic benefits. However, due to the fundamental different mechanisms of action between antiviral drugs and vaccines, such integration remains highly challenging, and no prior studies have addressed this concept. In response, Professor Zhen Liu’s research group at Nanjing University, in collaboration with leading external institutions, has actively explored and developed a brand-new multifunctional antiviral nanomedicine capable of both rapid viral inhibition and long-term prophylactic protection.
Based on the team's previous research foundation, by fully leveraging the feature of high-mannose glycan modification of high dense on viral glycan-shield, a novel broad-spectrum antiviral photothermal nanomedicine was developed, which integrates a dual antiviral action of rapid viral inhibition and long-term prevention towards a series of viruses (Figure 1). This nanomedicine is a rationally engineered photothermal gold nanorod capable of targeting the glycan-shield of various viruses and exerting multiple unparalleled antiviral mechanisms, i.e., blocking virus-cell attachment, inducing viral aggregation, enhancing macrophage phagocytosis, promoting virions lysis, and initiating immune response.As such, it exhibits potent and broad-spectrum antiviral efficacy toward a variety of viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its major variants, lassa virus (LASV) and porcine deltacoronavirus (PDCoV), with EC50 value as low as tens of pM level and nearly 100% inhibition rate.Importantly, in vivo experiments showed that intranasal administration combined with near-infrared (NIR) laser irradiation rapidly inactivated viral particles in the nasal cavity and significantly suppressed virus-induced inflammation. Furthermore, the resulting viral fragments effectively stimulated the host immune system, inducing the production of protective immunoglobulins IgG and IgA. In viral rechallenge experiments, this immune response endowed significant protection against reinfection. Thus, as a proof-of-concept, this study provides new insights and evidences for the design of “two-way player” antiviral agents that can simultaneously treat and prevent viral infections.
Figure 1. Schematic illustration of the broad-spectrum rapid inhibition and vaccine-like protection toward viruses by hypervalent and photothermal high mannose-targeting nanomedicine.
Firstly, gold nanorods (AuNRs) with excellent photothermal properties were synthesized and functionalized with high-mannose-targeting nucleic acid aptamers (AuNR-APT) on their surface. This modification enabled effective binding to the viral glycan-shield, thereby achieving broad-spectrum antiviral activity. The resulting AuNR-APT nanoparticles exhibited good monodispersity, and elemental mapping analysis confirmed the successful surface modification with both the aptamers and polyethylene glycol (PEG). Furthermore, characterization experiments demonstrated that AuNR-APT possessed outstanding photothermal stability and serum stability. Binding assays at both the protein and cellular levels confirmed that AuNR-APT could specifically and effectively bind to substrates with high-mannose overexpression (Figure 2).
Figure 2. Characterization of synthesis, photothermal property, stability, and binding affinity of AuNR-APT.
Secondly, a series of in vitro experiments demonstrated that AuNR-APT exerts multiple antiviral mechanisms at the cellular level, including: blocking virus-cell attachment, inducing viral aggregation, enhancing macrophage phagocytosis, and promoting virions lysis (Figure 3). Supported by these multifaceted antiviral mechanisms, AuNR-APT effectively inhibited the infection of host cells by a range of viruses, including SARS-CoV-2 and its major variants, Lassa virus (LASV), and porcine deltacoronavirus (PDCoV) (Figure 4).
Figure 3. Verification of multiple antiviral mechanisms of AuNR-APT.
Figure 4. Broad-spectrum antiviral capability of AuNR-APT.
Finally, in vivo studies demonstrated that AuNR-APT was capable of rapidly disrupting live viruses inhaled through the nasal cavity, thereby effectively controlling inflammation in mice (Figure 5). Moreover, the viral fragments generated by photothermal disruption efficiently activated the host immune response, leading to robust immunological protection. Upon viral rechallenge, treated mice exhibited significant inhibition of viral infection, confirming the long-term protective efficacy of AuNR-APT (Figure 6).
Figure 5. In vivo virus inhibition performance of high-mannose targeting hypervalent AuNR-APT.
Figure 6. In vivo vaccine-like protection effect of high-mannose targeting hypervalent AuNR-APT.
This work, entitled “An Intranasal Nanomedicine Functions as Both Potent Broad-spectrum Viral Inhibitor and Quasi-Vaccine”, was recently published as a research article in Advanced Functional Materials, a leading journal in materials science under Wiley. Professor Zhen Liu fromthe School of Chemistry and Chemical Engineering at Nanjing University and Professor Bin Li from the Institute of Veterinary Medicine at Jiangsu Academy of Agricultural Sciences are the corresponding authors, with Ph.D. candidates Jingran Chen and Ying Li serving as the first authors. This research was supported by the Key Grant from the National Natural Science Foundation of China, the National Key R&D Program from the Ministry of Science and Technology of China, the Research Excellence Program of Nanjing University, the Program for Outstanding PhD Candidates of Nanjing University and the Jiangsu Agriculture Science and Technology Innovation Fund.
Recently, this work was reported by Advanced Science News, the official science news platform of Wiley. Advanced Science News highlights significant and cutting-edge research published in Wiley’s portfolio of academic journals.
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https://doi.org/10.1002/adfm.202501533