Nanotechnology in COVID-19 prevention, diagnosis, and treatment: a comprehensive review

Abstract

The worst of the COVID-19 (coronavirus disease 2019) pandemic may be over, but its impact continues to be felt worldwide. During the outbreak, medical regulatory authorities introduced several principles for outbreak control, with the World Health Organization emphasizing three key strategies: prevention, early detection, and treatment. In this context, technological advancements have played a critical role, particularly nanotechnology, which has emerged as a promising platform for medical innovation. Its applications span multiple sectors, including healthcare, environmental protection, and diagnostics. These applications offer unmatched potential to enhance personal protective equipment, develop antiviral surface coatings, and engineer rapid point-of-care diagnostics. Nanotechnology contributed significantly to combating COVID-19, enhancing prevention through nanofiber-enhanced masks and nanoparticle-based disinfectants; facilitating diagnosis via gold nanoparticles (AuNPs) and magnetic nanoparticle biosensors, quantum dots, and artificial intelligence-integrated nanosensors; and supporting treatment efforts through lipid nanoparticle (LNP) vaccines, virus-like particles, and targeted drug delivery systems. We highlight key nanomaterials such as silver nanoparticles, copper nanoparticles, AuNPs, zinc oxide nanoparticles, and selenium nanoparticles, alongside advanced formulations like LNPs and polymeric nanocarriers, exploring their mechanisms of viral inactivation, sensitive detection, and controlled delivery of therapeutics. Furthermore, this review addresses critical regulatory and translational challenges and post-pandemic adaptations of nanotechnologies for emerging viral threats.

Background

Nanotechnology is one of the most promising technologies of the twenty-first century. It involves transforming nanoscience theory into practical applications by measuring, manipulating, regulating, and creating materials at the nanoscale [1, 2]. Recent advancements have enabled the development of nanotechnology-based tools capable of targeting and disabling COVID-19 (coronavirus disease 2019) [3, 4]. Key applications include infection-proof personal protective equipment (PPE) for healthcare workers, nano-based antiviral agents with enhanced efficacy and reduced toxicity, and nanosensors for faster, more sensitive pathogen detection. These solutions are widely implemented globally [5, 6].

Nanotechnology-based solutions for COVID-19—including vaccines, PPE, antiviral coatings, and diagnostics—offer significant promise but pose safety challenges. For example, nanoparticle vaccines have been linked to autoimmune responses, menstrual irregularities, and side effects associated with ingredients such as polyethylene glycol [7], while their long-term effects remain poorly understood. Similarly, although nanomaterial-enhanced PPE and antiviral coatings [8] may improve protection, issues such as barrier device complications [9] and biocompatibility concerns with 3D-printed components [10] persist. Moreover, despite the rapid and sensitive detection enabled by nanodiagnostics, their in vivo safety profiles are underexplored [3, 11].

Overall, extensive research has been conducted on the application of nanotechnology to combat COVID-19, particularly in prevention, diagnostic testing, and treatment. Despite a wealth of reviews on this topic, several critical gaps remain. Most existing reviews [5, 12–17] focus on nanomaterials for detection, disinfection, vaccines, and therapeutics, but often overlook emerging platforms such as nanozymes, exosome-mimetic carriers, and nanofibers, as well as regulatory and translational challenges. Although some papers [18, 19] briefly address conventional topics like intranasal drug delivery and U.S. Food and Drug Administration (FDA)-approved systems, they provide limited coverage of newer, technology-driven areas such as artificial intelligence (AI)-based nanosensors. This review addresses these gaps by comprehensively summarizing nanotechnology applications in the fight against COVID-19, ranging from established approaches in virus prevention, diagnosis, and treatment to emerging platforms, and examining key regulatory and translational challenges. In addition, it discusses clinical case studies and translational outcomes, regulatory frameworks by the FDA and European Medicines Agency (EMA), implementation challenges in low- and middle-income countries (LMICs), the environmental impact of widespread nanoparticle use, and post-pandemic adaptations of nanotechnologies for future viral threats. Figure 1 below illustrates the range of nanotechnology applications in the battle against COVID-19.

Fig. 1.

Exploring the multifaceted role of nanotechnology in addressing COVID-19: A visual overview of preventive, diagnostic, and therapeutic applications

Origin and transmission of COVID-19

In 1965, researchers discovered the first coronavirus, known as B814, which was associated with the respiratory tract of adults exhibiting symptoms of the common cold [20]. In early December 2019, a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first identified in China; it is the causative agent of COVID-19. It is believed to have originated from the Huanan seafood market in Wuhan, a live-animal market where multiple species were sold in proximity. Since then, the virus has spread rapidly to over 109 countries [21]. Although the exact origin of SARS-CoV-2 remains uncertain, genomic studies indicate that bats are the primary reservoir for the virus [22]. COVID-19 can cause severe illness and is known for its high transmissibility. The main transmission routes include respiratory droplets expelled when infected individuals cough, sneeze, or breathe [21, 23].

Additionally, droplets and aerosols from infected individuals can contaminate surfaces, and touching one’s face after contact with such surfaces may lead to viral exposure. To prevent the spread of the illness, infected individuals should maintain a distance of at least one meter (approximately 3 feet) from healthy individuals and practice good hand hygiene [23, 24]. Figure 2 illustrates the hypothesized origins of SARS-CoV-2, based on a recent report by a scientific committee convened by the World Health Organization (WHO) [25]. The report concludes that a zoonotic origin, involving spillover from animals to humans, is the best-supported hypothesis, while alternative explanations remain highly speculative.

Fig. 2.

Tracing the speculative origins of SARS-CoV-2

Comparison of SARS-CoV-1 and SARS-CoV-2

The coronavirus, severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), triggered an epidemic in 2002, rapidly escalating into a global pandemic by 2003 [26, 27]. SARS-CoV-2 caused a global pandemic in 2020 and continued to impact populations into 2021. SARS-CoV-2 infection leads to COVID-19, a potentially fatal respiratory disease [27, 28]. SARS-CoV-2 is a large, enveloped, positive-sense, single-stranded RNA virus containing nucleocapsid proteins. Its structure is similar to that of SARS-CoV-1, with a diameter ranging from 80 to 140 nm [29]. Although the SARS-CoV-1 outbreak was short-lived and concluded in June 2003, several studies have shown that it carried a significant mortality risk. According to previously reported data [30], the global fatality rate was 9.6%, with 8098 SARS-CoV-1 cases and 774 fatalities. As of June 1, 2025, there were 778 million confirmed COVID-19 cases and 7 million deaths [31]. Figure 3 illustrates the stability of SARS-CoV-1 and SARS-CoV-2 on different surfaces.

Fig. 3.

Stability of SARS-CoV-1 and SARS-CoV-2 on different surfaces (based on van Doremalen et al. 2020 [34])

Understanding the stability of pandemic viruses on different surfaces is crucial for identifying transmission risks and implementing adequate hygiene precautions. According to Fig. 3, SARS-CoV-1 and SARS-CoV-2 exhibited similar stability for up to 3 h in aerosol form and 72 h on plastic and stainless steel surfaces. Compared to SARS-CoV-1, SARS-CoV-2 is more stable on cardboard. These observations suggest that SARS-CoV-2 may persist longer on cardboard, plastic, and stainless steel, potentially increasing the risk of fomite-based transmission. Insights into viral surface stability can inform targeted mitigation strategies, such as improved disinfection routines in shared environments and choosing materials less conducive to viral survival [32–34].

Application of nanotechnology in fighting COVID-19

According to recent research, nanomaterials play vital roles in diagnosing, treating, and preventing viral infections, including SARS-CoV-2. COVID-19 can be diagnosed using enzyme-based assays and point-of-care tests; its transmission can be reduced through the use of gloves, masks, disinfectants, and antiviral surface coatings; and it can be managed effectively with vaccines and targeted drug delivery systems [35–37]. Nanomaterials’ diverse physical and chemical properties demonstrate high adaptability and efficacy against SARS-CoV-2. In the following section, we highlight recent applications of nanomaterials in combating COVID-19.

Nanotechnology in the prevention of COVID-19

Prevention is a critical step in controlling the rapid spread of any infectious disease. During the COVID-19 pandemic, the WHO recommended various preventive measures. Among these, nanomaterials have played a significant role through their incorporation into PPE, including masks, gloves, and protective clothing [38, 39].

Nano-antiviral agents against SARS-CoV-2

Antivirals are substances specifically designed to combat viral diseases. They may also enhance the immune system’s ability to defend against pathogens. Research has demonstrated that using nanoparticles as antiviral agents against SARS-CoV-2 has yielded promising results. The nanoscale interaction between engineered nanomaterials and viral particles has emerged as a critical focus of antiviral strategy development [40]. At the nanoscale, viruses are biological entities that invade host cells, while nanomaterials are engineered to perform specific antiviral functions. Viral surface proteins bind to host cell receptors, facilitating entry and subsequent release of viral genetic material. This mechanism leads to host cell damage and systemic viral spread by hijacking the host’s replication machinery [39, 40]. In contrast, nanoparticles are synthesized to target and neutralize viruses through size-specific, surface-modified, and functionalized mechanisms [41].

Silver nanoparticles (AgNPs)

According to a study by Salleh et al. (2020), AgNPs are highly effective against viruses and bacteria. Some research has demonstrated that these particles can prevent viruses from binding to host cells. AgNPs may inhibit the replication of SARS-CoV-2 by binding to and altering the structure of viral surface proteins [42]. Furthermore, in vivo toxicological studies conducted by Pilaquinga et al. [43] support the extrapolation of dosage data to humans to determine the primary routes of exposure. Comparisons of the in vivo behavior of SARS-CoV-2 to other viruses suggest that AgNPs hold promise as a potential therapeutic option [43].

Copper nanoparticles (CuNPs)

A study on CuNPs by Govind et al. [44] examined their ability to reduce coronavirus transmission on surfaces. Research has shown that CuNPs can effectively inactivate coronaviruses by disrupting their viral envelope [44]. This disruption renders the virus non-infectious, thereby preventing further spread. Following these findings, CuNPs have been incorporated into disinfectants and surface coatings to reduce coronavirus transmission in high-contact environments. Studies have further demonstrated that copper-based surfaces are highly effective at deactivating SARS-CoV-2 [44, 45].

Gold nanoparticles (AuNPs)

Owing to their exceptional electrical, optical, and catalytic properties, strong surface plasmon resonance, and high potential for bioconjugation, AuNPs are among the most widely employed nanomaterials in viral detection platforms. By modifying their size and structure or incorporating other materials, AuNPs with a large surface area can also enhance their antiviral and antibacterial properties. When functionalized and combined with existing antiviral agents, AuNPs have been shown to improve antiviral efficacy against specific pathogens. In this context, a study by Sarkar et al. [46] demonstrated that AuNPs can interact with viral RNA and proteins, disrupting viral replication and reducing viral load.

Zinc oxide nanoparticles (ZnONPs)

Among the most promising antiviral nanoparticles, ZnONPs have long been recognized for their capacity to inhibit viral replication through multiple mechanisms. These include blocking viral proteases and interfering with transcription and translation processes essential to viral genome expression. The versatility of zinc makes it a strong candidate for targeting a broad spectrum of viruses, including SARS-CoV-2. Research has shown that zinc ions can reduce the infectivity of SARS-CoV-2, suggesting a role in preventing virus transmission when applied to frequently touched surfaces such as doorknobs and railings [47, 48].

Selenium nanoparticles (SeNPs)

Selenium has long been recognized for its antiviral properties and is associated with improved outcomes in patients with COVID-19 [49]. Notably, ebselen, a selenium-based compound, has shown antiviral activity against SARS-CoV-2. Given the low toxicity, antioxidant capacity, and immunomodulatory properties of SeNPs, continued investigation into their therapeutic potential against SARS-CoV-2 is warranted and timely. SeNPs represent a promising strategy for mitigating the effects of the COVID-19 pandemic [50], owing to their anti-inflammatory, antifibrotic, and potent immunomodulatory activities. Moreover, their demonstrated ability to inhibit viral and microbial infections positions them as strong candidates for developing novel antiviral therapies targeting COVID-19.

Comparative performance of nanoparticle systems

The literature does not provide sufficient information to directly compare the performance of different nanoparticle systems (AgNPs, CuNPs, AuNPs, ZnONPs, SeNPs) specifically for COVID-19 applications. Hence, only discrete studies on nanoparticles can be compared. AgNPs have shown promising potential in combating COVID-19 due to their strong antimicrobial, anti-cancer, and antiviral properties. They can produce free radicals and ROS, inducing apoptosis and preventing viral contamination [51]. AuNPs are widely used in the medical field and have shown potential in various biomedical applications, including imaging, diagnosis, and treatment [52]. While not explicitly mentioned for COVID-19, AuNPs have been used in developing new diagnostic and therapeutic strategies in nanomedicine, such as drug carriers, agents in radio and phototherapy, and bioimaging for image diagnosis [52]. CuNPs and ZnONPs have demonstrated antibacterial properties [53, 54], potentially relevant in managing secondary bacterial infections associated with COVID-19. Ag-ZnO composite nanoparticles have demonstrated rapid wound-healing properties in animal models, outperforming pure AgNPs [55]. Various metal-based nanoparticles used as antiviral agents are summarized in Table 1.

Table 1.

Metal and metal oxide nanoparticles with antiviral activity against COVID-19

Nanoparticle class	Antiviral mechanism	Efficacy/Significant concentration	Toxicity/Safety profile	Reference
AgNPs	Bind viral spike proteins, blocking attachment	Pseudovirus neutralization in the presence of surfactant (unmodified AgNPs) at 50 µg/mL	Non-cytotoxic to BEAS-2B and primary nasal cells at 50 µg/mL; biocompatible with lung surfactant	[56]
Copper oxide (CuO/Cu4O) nanoparticles (CuONPs)	Contact inactivation via electrostatic attraction Solid-state ROS catalysis at high surface area coatings	99.8% inactivation in 30 min; 99.9% in 60 min on 30 µm thick CuO films	LD50 = 2000–2500 mg/kg (oral/dermal, rat); no cytotoxicity in A549/HeLa at active conditions	[57]
CuNPs in paint	Release of Cu⁺/Cu2⁺ ions; ROS-mediated virion damage	97.8% inactivation in 30 min; > 99.995% in 60 min on stainless steel painted with 1–5 wt% CuNPs	Favourable environmental safety for surfaces; systemic toxicology pending; coating minimizes exposure	[58]
AuNPs	Multivalent binding to viral surface proteins; steric blocking of attachment Ligand-mediated capsid deformation	> 80% human coronavirus OC43 inhibition at 2 nM (sulfonate–functionalized AuNPs) Negligible direct SARS-CoV-2 surrogate activity at ≤ 300 µg/mL	Non-toxic in vivo up to 800 µg/mL; in vitro cytotoxicity in keratinocytes above 300 µg/mL; biodistribution effects require further study	[59–61]
ZnONPs	ROS generation; photocatalysis under UV	≥ 106-fold Delta/Omicron reduction at 20 mg/mL after 1 h	biocompatible up to 20 mg/mL in Calu-3 cells	[48]
Titanium dioxide (TiO2) Nanotubes	Photocatalytic ROS (·OH, O2−) under UV causing oxidative damage - Direct oxidative inactivation at high surface area	IC50= 568.6 ng/mL; CC50 = 399.1 ng/mL (SI ≈ 0.7) in vitro; 96% inactivation within minutes under UV, ~ 99.99% at 6 h (HCoV-NL63 surrogate)	Potential hepatic/renal toxicity at oral doses (< 100 nm) in animals; dermal/inhalation safety under repeated exposure not fully determined	[62, 63]
Iron oxide (Fe4O4/FeO(OH)) nanoparticles	Alter iron metabolism; ROS generation; binding to viral thiols	> 90% SARS-CoV-2 inhibition at ≤ 100 µg/mL DMSA-IONP-10 in vitro; ~ 1 log lung viral load reduction in mice at 0.16 mg Fe/injection	DMSA-IONP-10 biocompatible in mice at multiple doses; transient organ accumulation without mortality; human IONPs low acute toxicity	[64]
Cerium oxide (CeO2) nanoparticles	Surface-mediated protein inactivation; ROS quenching/regeneration; electrostatic viral binding	Significant PFU reduction at 20 mg Ce/L after 1 h; superior efficacy vs. AgNPs at equal doses	No cytotoxicity up to 100 mg Ce/L; minimal antibacterial effects avoid dysbiosis	[65]
SeNPs	Inhibition of viral proteases; redox modulation; immunopotentiation via selenoproteins; cytokine-storm attenuation	Ebselen IC50 ≈ 0.67 µM vs. Mpro; SeNP coatings inhibit entry at ≤ 1 µg/cm2; improved COVID-19 recovery in mice	Lower toxicity vs. sodium selenite; narrow oral window mitigated by nanoparticle dosing; immunomodulatory benefits with minimal side effects	[50, 66]
Magnesium oxide (MgO) nanoparticles	ROS generation; membrane disruption	90% reduction in PFU at 2.4 – 10 mg/mL IC50 on HepG2 cells = 23.34 mg/mL	low toxicity and good biocompatibility	[67, 68]
Cobalt oxide (Co3O4) nanoparticles	Ion release; ROS; membrane binding; fiber-mediated virucidal barrier (e.g., PPE fabrics)	moderate antiviral activity at 25–100 mg/mL IC50 on melanoma A-375 cells = 303.80 µg/mL	Trojan horse toxicity mechanism	[69–72]
Other emerging/Composite nanoparticles	Photocatalysis (TiO2/Ti coating) Inhibition of binding of SARS-CoV-2 spike proteins to ACE2 receptor (nanoparticle composite TPNT1 – mixture of AuNP, AgNP, ZnONP & ClO2)	TiO2/Ti photocatalyst coating balls: 99.99% decrease rate for SARS-CoV-2 SI for TPNT1 > 10 for Vero E6 cells	TiO2 is non-toxic & chemically stable; can be applied in working spaces without evacuating people Safe doses for TPNT1 not yet established due to insufficient toxicological data	[73, 74]

ACE2 = Angiotensin-converting enzyme 2; BEAS-2B = human bronchial epithelial cell line; CC₅₀= half-maximal cytotoxic concentration; DMSA-IONP = dimercaptosuccinic acid iron oxide nanoparticle; HepG2 = hepatoblastoma cell line; IC₅₀ = half-maximal inhibitory concentration; LD₅₀ = Lethal Dose, 50%; M^pro= SARS-CoV-2 main protease; PFU = plaque-forming units; ROS = reactive oxygen species; SI = selectivity index (CC₅₀/IC₅₀)

PPE

Ensuring a safe working environment involves using PPE as a physical barrier against viral infections [75, 76]. Proper use of PPE, including face masks and gloves, remains one of the most effective strategies for preventing the transmission of COVID-19 [75, 77]. Face masks, laboratory coats, and medical aprons have been nanoengineered to enhance their functionality by adding hydrophobic and antibacterial properties while preserving material texture and breathability [77, 78].

In traditional masks, the fiber diameter ranges from approximately 10–30 μm, which is significantly larger than the size of many viruses, allowing viral particles to pass through these pores. As a result, such masks may be inadequate for high-risk environments [75]. In addition, many healthcare workers experience skin irritation or damage due to prolonged use of conventional face masks [79]. Masks enhanced with nanomaterials, such as nanofibers, offer improved comfort and can effectively filter particles smaller than 50 nm. These advanced materials also reduce pressure and breathing resistance, making them considerably more effective than traditional surgical masks. Figure 4 illustrates various types of PPE and their respective functions. For example, N95/FFP2 face masks are generally effective against particles ranging from 100–300 nm in size [75]. Another strategy to improve protection is the incorporation of nanoparticles, such as CuNPs and AgNPs, onto mask fiber surfaces. Integrating nanomaterials into PPE provides substantial benefits, including antimicrobial and antiviral properties that help block, inactivate, or destroy pathogens [80].

Fig. 4.

Nanotechnology applications of PPE

PPE incorporating nanomaterials relies on advanced engineering technologies to embed these materials into fabric, enhancing antiviral and protective properties [76]. In addition to direct integration, another approach involves coating or impregnating the fabric with nanomaterials using dip coating, spray coating, and layer-by-layer assembly techniques. Precise control over nanoparticle size and distribution within the fabric matrix is essential to optimize both performance and durability of these PPE items [81, 82].

Several mechanisms contribute to viral inhibition through nanomaterial-embedded PPE. First, viruses can be directly inactivated upon contact with nanomaterials, such as AgNPs, due to their inherent antiviral properties [83]. Second, nanomaterials can form physical barriers on the fabric surface that block viral particles from adhering to or penetrating the material. Additionally, some nanomaterials reduce viral viability by inducing oxidative stress or triggering localized immune responses [84]. A summary of various nanoparticles incorporated into PPE to prevent viral transmission is presented in Table 2.

Table 2.

Nanomaterial-embedded PPE against the spread of the COVID-19 virus

Types of nanoparticles	Methods of embedding/Size of nanoparticles	Methods of testing	Advantages	References
AgNPs	Electrospinning, 10–100 nm	In vitro viral assays, fabric performance tests	Reduction in viral infectivity, extended use time, and moderate cost	[80]
CuONPs	Dip coating, 20–200 nm	Viral transmission studies, fabric durability tests	Inhibition of viral transmission, long-lasting protection, and affordable cost	[58]
TiO2NPs*	Spray coating, 5–50 nm	Antiviral efficacy assays, safety assessment	Effective virus deactivation, comfortable wear, and safety verified	[85]

^*TiO₂ nanoparticles

Surface coatings

Nanoparticles possess antiviral properties that can be integrated into masks, disinfectants, coatings, and filters to help prevent the spread of COVID-19. These nanoparticles have been shown to enhance the permeability of viral membranes in several studies [86–88]. Nanoparticle-based coatings are commonly applied in PPE and are available in various formulations. AgNPs exhibit substantial toxicity against a broad spectrum of bacteria while remaining non-toxic primarily to human cells and displaying long-term stability. They are recognized for their self-cleaning, antibacterial, and antiviral properties [89]. Notably, AgNPs smaller than 10 nm have demonstrated antiviral activity against SARS-CoV-2.

Furthermore, natural and synthetic textiles have been functionalized with AgNPs and other metal-based nanomaterials, including copper, zinc, tin, titanium, and gold. As previously mentioned, the antibacterial activity of CuONPs on textile materials against Gram-positive and Gram-negative bacteria is attributed to three primary mechanisms: generation of ROS, direct interaction with bacterial membranes, and the release of copper ions [90]. Disinfecting high-contact surfaces is essential, as these areas are frequently contaminated with viruses. Applying antiviral coatings to such surfaces can significantly reduce the transmission of SARS-CoV-2 and other pathogens.

Face masks

Face masks and respirators are essential for limiting the transmission of COVID-19 via droplets and aerosols. Recent innovations in mask design have focused on incorporating nanoparticles to impart biocidal properties. These modifications enhance material hydrophobicity, improving protection against virus-laden droplets and aerosols. However, a common trade-off for these enhancements is reduced breathability [91, 92].

Face shields

Nanoparticle-coated face shields offer protection against respiratory droplets and aerosols, serving as an additional barrier against viral exposure [93]. Classified as PPE, face shields are used by frontline clinicians and healthcare workers to protect against infectious body fluids and airborne particles. These shields are primarily made from polycarbonate, which provides excellent optical clarity and mechanical performance across ultraviolet, visible, and infrared wavelengths [94]. Face shields function as transparent barriers that cover the face and eyes, offering comfort, ease of use, and enhanced protection. Nanoparticle-coated face shields may be a more comfortable and potentially more effective alternative to masks in specific settings. The nanoparticle coating captures and neutralizes viral particles, reducing the likelihood of transmission through the eyes and facial surfaces. This ability to capture and neutralize viral particles offers significant protection, especially in high-risk environments such as healthcare facilities [93–95].

Nanozyme-coated surfaces for viral inactivation

Nanomaterials have shown promising potential for inactivating SARS-CoV-2 and preventing its spread on surfaces. Several studies have explored using nanoparticles and nanostructured surfaces for this purpose. Nanostructured anionic polymers have demonstrated rapid inactivation of coronaviruses, including SARS-CoV-2, through a pH-drop mechanism at the polymer-pathogen interface. These polymers can inactivate the virus within minutes when applied to frequently touched surfaces [96]. Similarly, photothermal nanoparticles conjugated with neutralizing antibodies have shown the ability to capture and inactivate SARS-CoV-2 pseudoviruses, blocking viral entry into host cells [97, 98].

Interestingly, nanostructured aluminum alloy surfaces have also exhibited virus-inactivating properties. A study found that nanostructured Al6063 alloy surfaces could achieve a 5-log reduction in viable SARS-CoV-2 after 6 h of exposure compared to flat surfaces [99]. These findings suggest that engineered nanostructured surfaces could reduce viral transmission in healthcare and public spaces. Various nanomaterial-based approaches have shown promise for inactivating SARS-CoV-2 on surfaces. These include nanostructured polymers, antibody-conjugated nanoparticles, and nanostructured metal surfaces. Further research and development in this area could lead to more effective and practical solutions for reducing surface transmission of SARS-CoV-2 in public spaces and healthcare settings.

Sanitizers

Compared with many other viruses, SARS-CoV-2 exhibits greater environmental stability, enabling it to persist on inanimate surfaces such as skin, fabric, metal, wood, plastic, and glass for several hours to several days. Disinfectants have been formulated to eliminate microorganisms and achieve sterilization by completely eradicating them from treated surfaces. Using disinfectants to reduce potential transmission pathways is a critical protective strategy against COVID-19. Common disinfectants used during the pandemic include oxidants, alcohol, formaldehyde, phenol, glutaraldehyde-based compounds, chlorine, and iodine-releasing agents [100, 101].

However, caution is warranted because frequent disinfectant use poses potential environmental and health risks, adversely affecting wildlife, ecosystems, and human well-being. Therefore, developing safer and more eco-friendly alternatives is essential [100]. The production of such alternatives represents a promising application of nanotechnology. Metal nanoparticles, such as silver, copper, and titanium, have demonstrated notable antiviral efficacy against SARS-CoV-2. In this context, the Nano-Tech Surface Company has developed a disinfectant based on nanopolymers incorporating AgNPs and TiO₂NPs. This formulation offers several advantages, including nonflammability, biodegradability, and environmental compatibility [3, 102].

Nanotechnology in the diagnosis of COVID-19

COVID-19 cannot be eradicated from all surfaces, and not all materials are amenable to nanomaterial-based coatings. Therefore, containing the spread of the virus requires rapid and reliable diagnosis of infected individuals [103]. Several conventional diagnostic methods based on analytical chemistry have been employed; however, these often suffer from low sensitivity, complex procedures, and delayed result interpretation [104]. In this context, nanotechnology-based diagnostic platforms offer improved virus detection outside living organisms with high specificity and selectivity [104, 105]. To enhance the performance of sensors, researchers have utilized the surface chemistry of nanocomposites, including carbon nanostructures, nanowires, nanorods, and nanoparticles [106].

COVID-19 has been diagnosed in clinical settings using nanotechnology-based products [107, 108]. These devices, point-of-care diagnostic tools, perform rapid virus detection via color change, target capture, and plasmonic response [109]. Composed of biocompatible nanomaterials, these devices gained significant attention during the pandemic due to their favorable thermal, electrical, and fluorescent properties [110–113]. The most widely used diagnostic nanoparticles for COVID-19 detection include carbon nanotubes (CNTs), magnetic nanoparticles (MNPs), AuNPs, and quantum dots (QDs), each described below.

MNPs for diagnosis

MNPs are among the most widely utilized nanoparticles for pathogen detection due to their unique characteristics, including small size, superior magnetic responsiveness, and excellent biological compatibility. Superpara-MNPs are particularly effective for viral detection [112]. These nanoparticles facilitate complementary RNA applications and streamline detection by enabling magnetic field-based extraction of targeted cDNA from samples [111]. Somvanshi et al. reported that MNPs, activated for RNA extraction, represent promising tools for COVID-19 detection [110]. Overall, these MNP platforms reduce the number of detection steps and offer strong potential for molecular-level COVID-19 detection.

AuNPs for diagnosis

Due to their pronounced color change associated with surface plasmon resonance shifts, AuNPs are the most widely used metal nanoparticles for coronavirus detection. They can be easily functionalized with various antibodies and antigens [114–117]. The color change of AuNPs upon binding to viral antibodies enables visual detection without sophisticated instrumentation. Currently, AuNPs are integrated into biosensor platforms for on-site detection, using antibodies specific to the SARS-CoV-2 spike protein. These biosensors are cost-effective and rapid alternatives to Reverse Transcription Polymerase Chain Reaction (RT-PCR) [116].

QDs for diagnosis

QDs are emerging as innovative fluorescent probes for COVID-19 detection via molecular imaging. Their distinct optical properties and tunable emission wavelengths make them ideal candidates for fluorescent labeling of SARS-CoV-2 [8, 118–120]. Ashiba et al. developed a QD-based biosensor capable of detecting viruses with high sensitivity [118]. In their study, the sensor optimized substrate autofluorescence on the chip, enabling detection of as few as 100 viral particles [8, 121, 122]. Additionally, several studies support the use of QD-conjugated RNA aptamer chips for the rapid and sensitive detection of the SARS-CoV nucleocapsid (N) protein [36, 123].

QD-based lateral flow immunoassays (LFIAs) represent the most clinically validated approach, achieving remarkable sensitivity improvements and enabling precise point-of-care testing for both viral antigens and antibodies. Recent studies have documented substantial performance improvements with QD-based diagnostics. A smartphone-integrated QD-barcode device achieved 90% clinical sensitivity and 100% specificity for SARS-CoV-2 detection, compared to only 34% sensitivity for conventional lateral flow assays [124]. These results represent a threefold improvement in clinical sensitivity due to approximately 140-fold greater analytical sensitivity than traditional methods [124]. Furthermore, QD-based immunochromatographic assays demonstrate 10–100 fold enhanced sensitivity compared to conventional colloidal gold tests, enabling the detection of anti-SARS-CoV-2 IgM/IgG at much lower concentrations [125].

Advanced QD-biosensors utilizing highly sensitive B-cell epitopes of SARS-CoV-2 have achieved detection limits as low as 100 pM, with superior diagnostic accuracy compared to traditional Enzyme-Linked Immunosorbent Assay (ELISA) methods [126]. These biosensors showed 92.3–98.1% positive detection rates for COVID-19 antibody-positive patients, with rapid results obtained within approximately 5 min [126]. A novel QD-based LFIA designed for neutralizing antibody detection achieved 85.23% sensitivity and 92.50% specificity with a 10 min turnaround time [127]. This technology enables rapid assessment of vaccine effectiveness across large populations, addressing critical public health needs for monitoring vaccination coverage and immune response durability [127].

QD technologies enable simultaneous detection of multiple viral targets and variants within single assays. The stable photoluminescence and narrow emission spectra of QDs facilitate multiplexed detection approaches, which are crucial for tracking epidemiological trends and identifying viral mutations [128]. Recent developments include multiple aptamer recognition-based QD LFIA that achieved detection limits of 1.427 pg/mL for nucleocapsid protein and demonstrated 86.67% positive detection rates in clinical samples, compared to 55.17% for commercial alternatives [129]. Comprehensive clinical evaluations have confirmed the practical utility of QD-based diagnostics. Studies involving hundreds of clinical samples consistently demonstrate superior performance to conventional methods, with significantly reduced false-negative rates and enhanced early detection capabilities [130, 131]. These innovations collectively establish QD technologies as transformative tools for COVID-19 diagnosis, offering an unprecedented combination of analytical precision, rapid turnaround times, portability, and scalability essential for effective pandemic response and ongoing surveillance efforts.

Carbon nanoparticles for diagnosis

Currently, carbon-based nanomaterials are extensively employed in COVID-19 diagnostics due to their high biocompatibility, stability, and suitability for biosensing and bioimaging applications [36, 121–123, 132]. According to Ma et al. and Ahmadi et al. CNTs are among the most effective materials for detecting respiratory viruses, including SARS-CoV-2 [133, 134]. Numerous reports confirm that carbon-based nanoparticles are used in optical sensors due to their strong affinity for SARS-CoV-2 spike proteins. In particular, single-walled CNTs (SWCNTs) can amplify fluorescence signals in the presence of target viral particles [119]. A comparison of different nanotechnology-based diagnostic platforms is presented in Fig. 5 and Table 3.

Fig. 5.

Innovative nanotechnology-based diagnosis of COVID-19: A rapid and sensitive detection method using nanoparticles

Table 3.

Comparison of current diagnostic methods for COVID-19

Methods	Principle	Advantage	Limit of detection	Reference
RT-PCR	Primer and fluorescent marker-based	Reliable/detects current viral infection	100 copies/mL	[135]
RT-LAMP	Primer-based: two to three pairs of primer can be used	Highly sensitive at constant temperature (60–65 °C)	80 copies/mL	[20]
ELISA	Antigen/antibody-based	Sensitive or good specificity	ELISA − 5 IU/mL	[136]
Nanoparticle-based methods	Gold nanoislands (AuNIs)–nucleic acid hybridization via thermo plasmonic heating	High specificity and sensitivity	AuNIs–0.22 pM	[116]

RT-LAMP = reverse-transcription loop-mediated isothermal amplification

AI-integrated nanosensors

AI-integrated nanosensors have shown significant potential for diagnosing COVID-19, offering rapid, sensitive, and accurate detection methods. A bio-inspired peptide-based electrochemical biosensor, integrated with machine learning algorithms, achieved 100% sensitivity, 80% specificity, and 90% accuracy in detecting SARS-CoV-2 in saliva samples. This non-invasive, portable solution combines AI and nanotechnology for efficient COVID-19 screening [137]. Similarly, SWCNT-based optical nanosensors functionalized with ACE2 proteins demonstrated a robust fluorescence response to SARS-CoV-2 spike proteins, offering a rapid detection method [138]. Integrating AI and machine learning with optical nanomaterial-enabled biosensors is proposed to enhance the efficiency of diagnostic systems for future pandemic scenarios [139]. These advanced diagnostic tools could be crucial in managing the spread of SARS-CoV-2 and other similar viruses.

A gold‐nanopatterned plasmonic metasurface was engineered via a genetic algorithm to maximize localized plasmonic enhancement and functionalized with SARS-CoV-2 DNA aptamers. Machine learning analysis of Raman spectra accurately distinguished positive from negative saliva samples with 95.2% sensitivity and specificity, and further discriminated among wild-type, Alpha, and Beta variants, enabling clinical diagnosis and variant surveillance in under 20 min [140]. A complementary approach employed a machine-learning-aided multiplexed nanoplasmonic biosensor that simultaneously quantified antibodies against ancestral and Omicron strains with epitope resolution. Training on sera from naïve, convalescent, vaccinated, and convalescent-vaccinated cohorts, the platform achieved complete concordance with epidemiological data in a masked trial of 100 samples, underscoring its utility for population-level immunity profiling and vaccine efficacy monitoring [141]. Electrochemical nanosensors augmented by deep learning have also advanced point-of-care testing. A surface-enhanced Raman scattering (SERS) sensor analyzed saliva spectra via a convolutional neural network to distinguish SARS-CoV-2–infected from healthy individuals with 89–92% accuracy, enabling non-invasive, rapid screening without labels or complex sample prep [142]. These AI-integrated nanosensing modalities combine ultralow limits of detection, real-time data processing, and portable form factors, offering critical enhancements over conventional assays, enabling early infection detection, variant differentiation, and large-scale surveillance—all essential for agile clinical decision-making and public health responses during the ongoing pandemic.

Nanotechnology in the treatment of COVID-19

Different nanotechnology-based therapeutics and vaccines have contributed significantly to the fight against COVID-19. Developing efficient nanocarriers and nanoproducts proved critical during the pandemic [136, 143].

Development of an effective nano-based Vaccine

During the COVID-19 pandemic, a wide range of vaccines were introduced globally to combat the virus, including Pfizer/BioNTech, Moderna, CoronaVac, BBIBP-CorV, CoviVac, Covaxin, Oxford–AstraZeneca (ChAdOx1 nCoV-19), Sputnik V, Johnson & Johnson, Convidicea, the RBD-Dimer, and the EpiVac Corona [144]. These nanotechnology-based vaccines offer advantages due to the high-quality nanomaterials used, which allow for precise control over particle size and surface modifications. Unlike traditional vaccines composed of inactivated or killed viruses, mRNA and other bioengineered vaccines can be easily and cost-effectively adapted to target emerging antigenic sites [145].

Enhanced protection, durability, immunogenicity, and targeted delivery represent critical parameters in the design of nanoparticle-based vaccine carriers [146]. Lipid nanoparticles (LNPs) gained widespread recognition due to their efficient manufacturing processes and the safe, successful delivery of mRNA vaccines during the pandemic [145]. Additionally, cell membrane-derived nanoparticles, such as exosomes, have shown promise for both therapeutic applications and vaccine development against viral infections [146–148]. Building on this, exosome-based nanovaccines and drug delivery systems have emerged as innovative approaches for combating COVID-19.

Exosome-based vaccines and theranostics

Exosomes are nano-sized, lipid bilayer vesicles that closely resemble viruses and are secreted by various cell types, including those of the respiratory tract. Their high biocompatibility, low immunogenicity, and ability to carry therapeutic cargo make them attractive for vaccine delivery and antiviral therapy [149]. Notably, mesenchymal stem cell-derived exosomes have shown potential to reduce cytokine storms, restore antiviral defenses, and promote lung tissue repair in COVID-19 cases. Engineered exosomes displaying the four key SARS-CoV-2 structural proteins, such as spike, membrane, nucleocapsid, and envelope, have been proposed to stimulate both humoral and cellular immunity, offering prospects for long-term protection [150]. Exosome platforms have rapidly advanced as vaccines and theranostic agents against COVID-19 by exploiting their innate biocompatibility, nanoscale delivery capacity, and immunomodulatory properties. In vaccinology, engineered exosomes displaying SARS-CoV-2 spike proteins on their surface elicit robust humoral and cellular immunity at nanogram antigen doses, exceeding the potency of conventional protein vaccines without requiring adjuvants. For example, Capricor’s StealthX™ exosome vaccine, presenting the Delta-variant spike, induced high neutralizing antibody titers against Delta and Omicron (BA.1 and BA.5), along with significant CD4⁺ and CD8⁺ T-cell responses, while using only nanograms of spike protein per dose, achieving broad variant cross-protection, room-temperature stability, and rapid manufacturing timelines comparable to mRNA platforms [151]. Similarly, inhalable exosome-like virus-like particles decorated with recombinant receptor-binding domains generated strong mucosal IgA and systemic IgG responses after intranasal administration, offering needle-free immunization with thermostability at ambient conditions [152].

In theranostics, exosomes serve dual diagnostic and therapeutic roles by carrying both imaging moieties and antiviral cargoes. Convalescent serum-derived exosomes loaded with SARS-CoV-2 mRNA have been proposed as point-of-care diagnostic vehicles, enabling concurrent antigen detection and personalized mRNA delivery to antigen‑presenting cells for booster immunization [153]. Moreover, mesenchymal stem cell-derived exosomes carrying anti-inflammatory miRNAs mitigate SARS-CoV-2-induced cytokine storms, reducing tumor necrosis factor-alpha (TNF-α), interleukin-6, interleukin-17, and interferon‐gamma release in peripheral blood mononuclear cells assays and improving lung histopathology in preclinical models, thereby combining therapeutic immunomodulation with potential imaging reporters for disease monitoring [154]. These exosome-based theranostics integrate real-time biodistribution tracking and tailored intervention, positioning them as transformative tools for simultaneous COVID-19 diagnosis, treatment, and monitoring within a single nanoscale platform.

mRNA Vaccines

The COVID-19 vaccines developed by Pfizer/BioNTech and Moderna use LNPs to encapsulate and deliver mRNA that encodes the spike protein of SARS-CoV-2, thereby triggering an immune response against the virus [155].

Virus-like particle (VLP) vaccines

Hepatitis B, influenza, norovirus, coronavirus, and human papillomavirus are infectious diseases for which VLP-based vaccines have been developed [156]. Research indicates that incorporating nanoparticles to generate immunogenic binding sites can enhance the immune response elicited by vaccine delivery systems. Additionally, VLPs are small, possess intrinsic adjuvant properties, and can elicit a stronger immune response than the native virus [157–159]. VLPs stimulate the production of various T cells and immunoglobulins by inducing diverse antigen–antibody reactions, thereby enhancing immune resistance [160, 161].

Nanoparticle-adjuvant vaccines

Adjuvants have been a standard component of vaccine formulations for several decades, boosting the immune system’s response to vaccine antigens. Recently, modern vaccine formulation strategies have increasingly emphasized the use of nanoadjuvants [162]. Several vaccines, including the Novavax-developed NanoFlu vaccine, incorporate nanoparticle-based adjuvants to enhance immune responses. These adjuvants, which may consist of various nanomaterials or aluminum-based nanoparticles, play essential roles in stimulating immunity and improving vaccine efficacy [163]. Through mechanisms such as enhanced immune stimulation, antigen protection, and improved presentation to antigen-presenting cells, nanoadjuvants can improve the efficacy of COVID-19 vaccines while minimizing toxicity and optimizing benefit-to-risk ratios [161]. Various nanoformulations used to develop COVID-19 vaccines are presented in Table 4.

Table 4.

Nanoformulations for effective COVID-19 vaccine development

Types of nanoparticles	Methods of synthesis	Methods of testing	Significant results	References
LNPs	Encapsulation of mRNA encoding viral antigens	In vitro cell culture assay, animal studies	Inductions of robust immune responses and protection against viral challenge	[155]
VLPs	Self-assembly of protein subunits to mimic viral structure	Animal studies, clinical trials	Generations of neutralizing antibodies and prevention of infections	[156]
Nanoparticle-based adjuvants	Incorporation of adjuvant nanoparticles in vaccine formulations	Immunological assay, clinical trials	Enhance immune responses and increase vaccine efficacy	[163]

Nano-based drug delivery systems

To ensure the effective delivery of nucleic acids at the cellular level, efficient delivery mechanisms such as nanocarriers are essential [164]. Various carriers, including lipid, protein, and polymer derivatives, have been investigated for mRNA delivery. The electrostatic adsorption of LNPs and their fusion with the plasma membrane are driven by the charge differential between positively charged LNPs and the negatively charged cell membrane. The anionic lipids in cells are believed to neutralize the charge of LNPs upon entry, facilitating the release of nucleic acids from the cationic carrier. This process disrupts the nanoparticle structure, resulting in a nonlamellar configuration, and reduces the electrostatic attraction between lipids and nucleic acids [165, 166]. In addition to antiviral agents such as metal nanoparticles, other nanomaterial-based products have been developed as drug delivery systems to combat COVID-19 [167, 168]. These systems encapsulate antiviral agents within biodegradable polymers, enabling targeted delivery and controlled release of therapeutic payloads. The following section discusses nano-based polymeric delivery systems for COVID-19 therapeutics, as outlined in Table 5 and supported by previous studies.

Table 5.

Polymeric drug-delivering agents against COVID-19

Polymeric agents	Methods of synthesis	Methods of testing	Mechanisms of action	References
PLGA	Emulsion/solvent evaporation method	In vitro cell culture assays, animal studies	Efficient encapsulation and targeted delivery of antiviral drugs and inhibition of viral replication	[169, 170]
Polymeric micelles	Self-assembly of block copolymers	In vivo animal studies	Enhanced bioavailability and therapeutic efficacy of antiviral drugs; reduction in viral load	[171]
Electrospun polymeric nanofibers	Electrospinning technique	In vitro viral capture assays, animal studies	Effective capture and neutralization of viral particles and prevention of viral transmissions	[172, 173]

PLGA = poly lactic-co-glycolic acid

Polymeric nanoparticles (polymeric-NPs)

Biodegradable polymeric-NPs are among the most promising drug delivery strategies for pulmonary/respiratory applications [174, 175]. Solid nanoparticles or nanocapsules encapsulate therapeutic substances within a polymeric matrix or adsorb them onto their surfaces [168, 174]. Among them, nanoparticles composed of PLGA or chitosan have been extensively studied. Yang et al. [170] explored formulations of chitosan/PLGA nanoparticles, which are widely used for drug delivery due to their finely tuned size distributions, enhancing mucoadhesion and biocompatibility [170]. Chitosan-based polymeric-NPs have garnered particular interest for intranasal therapy because of their non-toxic nature, high biocompatibility, strong ability to bind epithelial cells, and structural adaptability to various shapes and sizes. When combined with therapeutic compounds, chitosan can enhance polymeric-NP effectiveness under mucosal conditions and improve penetration across the mucosal membrane, potentially helping to prevent COVID-19 infections in the mucosal environment [169].

Polymeric micelles

Micellar formulations enable the delivery of poorly soluble antiviral drugs, primarily due to their ability to encapsulate such compounds. In COVID-19 treatment, drugs stored in the micellar core can accumulate at the infection site while being shielded from premature degradation [171].

Polymeric nanofibers

Nanofibers made from polymers have demonstrated significant potential in drug delivery systems, especially when fabricated as synthetic electrospun fibers loaded with pharmaceuticals. Their high surface area, tunable diameter and topology, porosity, functionalization capacity, and high encapsulation efficiency make them highly suitable for sustained drug release. One study reported that electrospun polyacrylonitrile nanofibers provided sustained drug release for up to 12 h. These electrospun fiber-based systems show great promise for COVID-19 therapy [172, 173].

Targeting infected cells or tissues is a key strategy that relies on nanoparticle synthesis. Traditionally, drugs cannot efficiently reach the infection sites without nanoparticle functionalization using ligands that bind to specific viral or cellular receptors [176]. Functionalizing drug delivery systems with nanotechnology-enhanced materials boosts therapeutic effectiveness while minimizing side effects. In this context, the unique characteristics of nano-based delivery systems, such as composition, luminescence, morphology, high surface-area-to-volume ratio, tunable size, and customizable active sites (e.g., mesoporous silica nanoparticles, AgNPs) have drawn growing attention [177–179].

Nanotechnology-modified drug delivery systems offer site-specific targeting, low toxicity, biodegradability, biocompatibility, and controlled release via polymeric, lipid-based, dendrimer, liposome, and micelle-based nanoparticles [180–182]. However, some nanomaterials have limitations. For example, CNTs may harm respiratory tissues and negatively impact lung function [183, 184]. Significant efforts have been made to extend drug release duration and improve the bioavailability of lipid-coated mesoporous silica nanoparticle-based therapeutics. These nanoparticle-based antiviral drugs have shown potent antiviral activity and low toxicity in in vivo studies [185–187].

Clinical case studies and translational outcomes

Translating nanotechnology-driven interventions into clinical practice has been a cornerstone of the global response to COVID-19, moving beyond in vitro promise to demonstrate real-world impact. The pivotal Phase III trials of LNP-formulated mRNA COVID-19 vaccines, BNT162b2 (Pfizer/BioNTech) and mRNA-1273 (Moderna), demonstrated robust efficacy and acceptable safety profiles in large, randomized, observer‐blinded, placebo‐controlled studies. In the BNT162b2 trial (N = 43,548), two 30 µg doses administered 21 days apart conferred 95% efficacy against laboratory‐confirmed COVID-19 beginning 7 days after the second dose, with comparable protection across age, sex, race, ethnicity, body‐mass index, and coexisting condition subgroups [188]. Only one of ten severe COVID-19 cases occurred in the vaccine group versus nine in the placebo group. They reported that adverse events were predominantly mild to moderate injection‐site pain, fatigue, and headache, with serious adverse events balanced between groups [188]. The mRNA-1273 coronavirus efficacy trial enrolled 30,351 adults receiving two 100 µg doses 28 days apart, achieving 94.1% efficacy against symptomatic, adjudicated COVID-19 ≥ 14 days after dose 2, with zero cases of severe disease or COVID-19–related death in vaccinees compared to 30 severe cases and one death in placebo recipients [189]. Both vaccines sustained efficacy across diverse populations and demonstrated favorable safety, supporting their emergency use and widespread deployment for pandemic control.

In a real‐world evaluation of AuNP–based rapid antigen testing, the Panbio™ COVID-19 Ag Rapid Test Device was deployed in primary healthcare centers in Valencia, Spain, as a point‐of‐care tool for symptomatic patients within seven days of symptom onset. In an operator‐blinded study of 412 individuals, paired nasopharyngeal swabs were collected for immediate Panbio testing and laboratory RT-PCR confirmation. The AuNP‐LFIA assay yielded results in 15 min and demonstrated 79.6% sensitivity and 100% specificity; sensitivity rose to 91.4% in high viral load samples and 80.4% in patients tested within five days of symptom onset, with specificity maintained at 99.8% [190]. Healthcare providers reported the test’s ease of use and minimal training requirements, while rapid results facilitated immediate isolation decisions and optimized RT-PCR resource allocation. This deployment underscores the clinical relevance of AuNP‐based antigen assays in community settings, offering a low‐cost, scalable solution with robust performance for early COVID-19 diagnosis, thereby enhancing pandemic surveillance and patient management in decentralized healthcare facilities.

Exosome‐based nanocarriers have shown promise in small‐scale human studies for cytokine‐storm mitigation in severe COVID-19. In a prospective, nonrandomized, open‐label cohort study (ExoFlo™), 24 patients with severe COVID-19 and moderate‐to‐severe acute respiratory distress syndrome received a single 15 mL intravenous infusion of bone marrow mesenchymal stem cell–derived exosomes [191]. All safety endpoints were met with no infusion‐related adverse events within 72 h. By day 14, overall survival was 83%, with 71% achieving full clinical recovery, 13% remaining critically ill but stable, and 16% deaths deemed unrelated to treatment. These first‐in‐human findings establish ExoFlo™ as a safe and potentially efficacious therapy for cytokine‐storm mitigation in critical COVID-19. These clinical case studies underscore the successful harnessing of nanotechnology to prevent, diagnose, and treat COVID-19. These translational outcomes lay a robust foundation for addressing future infectious threats.

Challenges

Challenges related to using nanotechnology products for fighting COVID-19 include ensuring efficacy against the virus while mitigating potential health and environmental risks [192]. In embedding and integrating nanomaterials into PPE, issues such as durability and effectiveness over time and contamination of the environment during use and disposal must be addressed [193]. Due to the urgent global need to end the COVID-19 pandemic, results on new therapeutics have been announced almost daily. Moreover, advances in the field of nanotechnology have brought it into the limelight, demonstrating that nanotechnology can be a cornerstone for addressing various health challenges in the future. Moreover, nanotechnology-based drugs are effective inside and outside cells, but their toxicity presents challenges [194].

Various nanoparticles, such as AgNPs, CuNPs, AuNPs, and ZnONPs, exhibit limitations related to cytotoxicity, inflammatory reactions, and potential environmental impacts. Cytotoxicity is a significant concern for many nanoparticles. AgNPs and AuNPs have been shown to decrease cell populations and increase macrophage size at concentrations  ≥  10 ppm [195]. ZnONPs also demonstrate cytotoxicity, which can be mitigated through surface modifications like PEGylation, reducing cellular uptake [196]. The cytotoxicity of nanoparticles is often size-dependent, with smaller particles generally exhibiting higher toxicity [197].

Inflammatory responses are another limitation. In macrophages, AuNPs, especially smaller ones, can up-regulate proinflammatory genes like interleukin-1, interleukin-6, and TNF-α [195]. AgNPs and CuNPs have also been shown to induce the excretion of inflammatory cytokines like interleukin-6 and interleukin-8 in human cell lines [197]. Interestingly, the formation of a protein corona on nanoparticles when exposed to biological fluids can significantly affect their cellular interactions and toxicity. For instance, citrate-capped AgNPs are readily coated by serum proteins, influencing their uptake and cytotoxicity. In contrast, oligo(ethylene glycol)-alkanethiol-capped AgNPs are more resistant to protein adsorption and show reduced uptake and toxicity [198].

While nanoparticles offer promising applications in various fields, their use is limited by concerns over cytotoxicity, inflammatory reactions, and potential environmental persistence. The extent of these limitations varies depending on factors such as particle size, surface coating, and composition. Ongoing research aims to mitigate these issues through surface modifications and developing more biocompatible nanoparticle formulations [199–201]. Despite these challenges, the substantial benefits, ranging from enhanced efficacy of PPE to improved therapeutic delivery, strongly suggest that the advantages of nanotechnology in combating COVID-19 outweigh its potential risks.

Regulatory and translational challenges

Nanotechnology promises to combat COVID-19 through prevention, diagnosis, and treatment, but several regulatory and practical challenges hinder its clinical translation. A key issue lies in manufacturing scale-up, as nanoparticle-based formulations, especially polymeric nanocarriers, are complex to reproduce consistently across batches [202]. Their multi-component nature demands precise engineering and robust techniques for reliable industrial-scale production [203]. Regulatory hurdles present additional barriers. Unlike conventional pharmaceuticals, nanomedicines require additional scrutiny due to their unique physicochemical properties and biological interactions [204]. Current regulatory frameworks often lack harmonized standards for assessing nanoparticle safety, particularly regarding immunotoxicity and long-term health effects [205]. Regulatory bodies are still evolving guidelines to ensure the safe use of nanomaterials in medical applications [206]. Other translational challenges include maintaining nanoparticle stability under physiological conditions, optimizing drug loading and release profiles, and accurately tracking biodistribution and clearance [207]. Safety concerns, particularly immune responses and organ accumulation, underscore the need for detailed pharmacokinetic and toxicity evaluations [208, 209]. Although antimicrobial peptides such as defensins, cathelicidins, and lactoferrin have shown effectiveness against SARS-CoV-2, their therapeutic potential is limited by challenges related to stability, toxicity, and efficient delivery systems [210].

Despite these challenges, notable advances have been made. LNP-based COVID-19 vaccines demonstrated the clinical viability of nanocarrier systems [211], and scalable diagnostic platforms have emerged [212]. However, most nanoparticle-related clinical trials remain in early stages [213], revealing a gap between innovation and application. Addressing these issues requires interdisciplinary collaboration, standardized testing protocols, and proactive regulatory development. A precautionary yet enabling approach is essential to safely translate nanotechnology from bench to bedside in the fight against COVID-19.

FDA and EMA regulatory frameworks for nanomedicines

Current regulatory guidance for nanomedicines is evolving but remains anchored to general medicinal product laws, with the FDA and EMA issuing supplementary documents that clarify nano-specific expectations while avoiding creating a separate legal class.

Under existing drug and biologic statutes, the FDA regulates nanomedicines via a risk-based, product-focused approach. Its 2022 final Guidance for Industry, “Drug Products, Including Biological Products, That Contain Nanomaterials,” sets out expectations for physicochemical characterization, identification of critical quality attributes, comparability protocols, and bridging strategies, when manufacturing changes alter nano-features [214]. Earlier overarching guidance asks sponsors to consider whether a product “involves the application of nanotechnology” based on size (~ 1–100 nm) or dimension-dependent properties, triggering deeper review [215]. Additional class documents, such as those on liposome drug products and continuous manufacturing discussion papers, expand on Chemistry, Manufacturing, and Controls (CMC), pharmacokinetic and labeling requirements, and encourage early engagement through the Emerging Technology Program [216]. Collectively, the FDA framework emphasizes case-by-case evaluation, use of International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) quality guidelines, and demonstration of safety and efficacy equivalence when nanoscale manipulation is used to repurpose existing actives [217].

The EMA likewise relies on the centralized marketing-authorization pathway in the European Union but has issued non-binding scientific guidelines and reflection papers through its Nanomedicines Expert Group. These documents cover intravenous liposomes, Fe₃O₄ nano-colloids, block-copolymer micelles, surface-coated parenteral nanomedicines and nanocrystals, detailing data requirements for quality, non-clinical bridging, and bioequivalence [218, 219]. A 2025 horizon-scanning report highlights forthcoming guidance on RNA-loaded LNPs and continuous-manufacturing control strategies, reaffirming that the benefit—risk balance is assessed against conventional standards for quality, safety, and efficacy [220]. The EMA, therefore, offers granular, modality-specific advice, but like the FDA, has stopped short of a dedicated “nano” legal category, preferring incremental refinement of existing directives.

Implementation challenges in LMICs

Despite these mature agency frameworks, the uptake and implementation of nanomedicines in LMICs lag markedly. High unit costs, proprietary supply chains, and cold-chain logistics—exemplified by mRNA-LNP COVID-19 vaccines—have created a “nano-divide” in which affluent nations secured three-quarters of nano-vaccine doses, versus negligible procurement by low-income countries [221]. Limited domestic manufacturing capacity and paucity of Good Manufacturing Practice facilities capable of nanoscale quality control compound affordability barriers [222]. Regulatory readiness is another obstacle: many LMIC authorities lack specialized metrology tools and trained reviewers for nano-specific CMC dossiers, prolonging approvals and deterring sponsors [223]. Clinical development patterns further reinforce inequity; fewer than half of industry nanomedicine trials occur in any LMIC, restricting local safety data and delaying access once products are licensed elsewhere [224]. African stakeholders cite fragmented innovation ecosystems, scarce venture finance, and technology-transfer bottlenecks as additional hurdles to translating laboratory successes into registered products [225].

Addressing these challenges will require coordinated technology-transfer hubs, multilateral financing to de-risk local fill-finish and lipid excipient manufacture, regional regulatory cooperation to pool expert review of nano-dossiers, and deliberate inclusion of LMIC sites in pivotal nanomedicine trials. Without such measures, sophisticated regulatory guidance in high-income jurisdictions risks widening access gaps rather than delivering the promised public-health benefits of nanotechnology.

Environmental impact of widespread nanoparticle use

Mass application of manufactured nanoparticles poses new dangers to terrestrial and aquatic ecosystems. In industry processes, nanoparticles such as AgNPs, TiO₂NPs, and CuONPs enter wastewater streams, often evading standard elimination methods and accumulating in effluents and sewage sludge [226]. Once released, these nanoparticles can undergo aggregation, dissolution, and surface transformations (e.g., sulfidation), altering their mobility and toxicity in receiving waters [226]. Their high surface reactivity enables them to adsorb and transport persistent organic pollutants and heavy metals, effectively acting as vectors facilitating contaminant dispersion throughout aquatic systems [227].

In soils, nanoparticles exhibit exceptional persistence and marked resistance to degradation over long timescales, depositing in solid fractions and pore waters [226, 228]. Their small size and surface functionalization often enhance colloidal stability, thereby promoting deeper transport into soil profiles and potential leaching into groundwater [229]. Accumulated nanoparticles can disrupt soil microbial communities by inhibiting key enzymatic processes such as acid phosphatase, β-glucosidase, nitrification, and nitrogen fixation. Such disruption leads to impaired nutrient cycling and reduced soil fertility [230]. For example, AgNPs have been shown to significantly reduce carbon and phosphorus-cycling enzyme activities, while CuONPs inhibit nitrification and denitrification pathways at environmentally relevant concentrations [230].

Moreover, chronic nanoparticle exposure can bioaccumulate in plants and soil invertebrates, and trophic transfer raises concerns for food-chain contamination and human health. The combined effects of altered soil structure, impaired microbial function, and vector-enhanced pollutant transport underscore the need for comprehensive life-cycle assessments and the development of sustainable design and regulation strategies to mitigate the long-term environmental footprint of nanotechnology.

Post-pandemic adaptations of nanotechnologies for emerging viral threats

Building on breakthroughs during the COVID-19 pandemic, nanotechnology platforms are being repurposed to tackle influenza, respiratory syncytial virus (RSV), and monkeypox. Lessons learned in rapid diagnostics, antiviral coatings, and flexible vaccine delivery inform next-generation countermeasures.

Retooling COVID-19 nanotech for influenza, RSV, and monkeypox

LNP–mRNA vaccines encoding the SARS-CoV-2 spike protein demonstrated rapid antigen deployment and favorable thermal stability. Similar platforms have been reformulated with influenza antigens, hemagglutinin (HA) stalk, neuraminidase (NA), M2, and nucleoprotein, to induce broad group 2 influenza immunity after a single low-dose injection, achieving cross-protection in mice against seasonal and avian strains in preclinical studies [231, 232]. RSV vaccines leveraging stabilized pre-fusion F protein in LNPs have entered Phase III trials, showing > 80% efficacy against severe RSV disease in older adults [233]. Monkeypox quadrivalent mRNA-LNP vaccines encoding A29L, M1R, A35R, and B6R elicited robust neutralizing antibodies and T-cell responses in mice, offering a blueprint for rapid response to orthopoxvirus outbreaks [234].

Case examples of adapted nanotechnologies

AgNPs integrated into air-filter media have been shown to inactivate aerosolized RSV in murine models. Intranasal inoculation of AgNP-coated filters reduced lung RSV loads by up to 55%, with minimal toxicity, suggesting applications in healthcare, HVAC (Heating, Ventilation, and Air Conditioning) systems to reduce RSV transmission [235]. Influenza diagnostics have adopted QD–based LFIA: QuantumPACK Easy devices achieved 80.9% sensitivity for influenza A and 83.7% for B versus 66.0% and 61.2% in AuNP assays, with 100% specificity and 10 min turnaround in 394 clinical samples [236]. Multiplexed QD-based LFIAs detect H5 and H9 subtypes at 0.016 and 0.25 hemagglutination units within 15 min, facilitating rapid subtype surveillance and early outbreak detection [237].

Platform flexibility for rapid variant response

LNP vaccines exhibit modularity: by swapping mRNA constructs, formulations can be rapidly updated for seasonal influenza or repurposed for emergent threats such as RSV or monkeypox, often within weeks rather than months [231, 234]. Similarly, AI-driven nanosensors originally trained on SARS-CoV-2 spike protein have been retrained on monkeypox surface glycoproteins, enabling a plasmonic metasurface–Raman platform to distinguish monkeypox variants with > 95% accuracy in saliva samples within 20 min. Convolutional neural networks applied to SERS spectra enable non-invasive, label-free screening. This illustrates the agility of data-driven nanodiagnostics in adapting to new viral pathogens.

Conclusions

COVID-19 has emphasized the urgent need for innovative countermeasures, and nanotechnology has already proven its value in antiviral coatings, advanced PPE, sensitive diagnostics, and targeted vaccine and drug delivery. Looking ahead, next-generation nanovaccines (e.g., VLPs and exosome-based platforms), AI-driven point-of-care nanosensors, and innovative theranostic systems that combine responsive drug release with real-time imaging hold particular promise. Realizing these advances will demand interdisciplinary collaboration among materials scientists, engineers, clinicians, and regulators, alongside standardized testing protocols and rigorously designed clinical trials, to ensure that nanotechnology supports our current pandemic response and fortifies preparedness for future viral threats.

Author contributions

M.D.: Writing—original draft, Writing—review and editing, conceptualization, and visualization; Y.S.: Writing—review and editing, conceptualization, supervision, validation, and visualization; J.P.R.: writing—review and editing, revision of the manuscript, conceptualization, supervision, and visualization; G.K.: writing—review and editing, revision of the manuscript, conceptualization; A.R.: conceptualization, supervision, validation, and visualization; D.E.: conceptualization, supervision, validation, and visualization. All the authors have read and agreed to the final version of the manuscript.

Funding

This research received no external funding.

Data availability

Data sharing is not applicable to this article, as no new data were generated or analyzed.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.