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Long COVID, a debilitating post-viral syndrome following SARS-CoV-2 infection, affects over 770 million individuals globally, manifesting as a multisystemic condition with significant socio-economic implications, estimated at USD 3.7 trillion in losses in the United States alone. Despite its profound impact, no definitive treatments have been established. This review comprehensively examines the pathophysiology of long COVID, highlighting its underlying causes such as viral persistence, dysregulated immune responses, and chronic inflammation. It evaluates the therapeutic potential of niclosamide, an FDA-approved antiparasitic drug, in addressing these mechanisms through its antiviral and anti-inflammatory properties. However, niclosamide’s clinical utility is hindered by poor solubility and bioavailability, challenges that have persisted for over six decades. Recent advances in nanotechnology offer a solution by enhancing niclosamide’s pharmacokinetics through nanoengineering techniques, such as solid lipid nanoparticles, liposomes, and inorganic nanohybrids. Preclinical studies demonstrate that nanoengineered niclosamide significantly improves solubility, bioavailability, and therapeutic efficacy, making it a viable candidate for clinical trials targeting long COVID. This article explores the mechanistic underpinnings of long COVID, the pharmacological advantages of nanoengineered niclosamide, and the regulatory, clinical, and economic considerations for its repurposing, providing a roadmap for its integration into global health strategies.
1. Introduction
1.1 Background and Rationale
Long COVID, also known as post-acute sequelae of SARS-CoV-2 infection (PASC), emerges as a chronic condition following the acute phase of COVID-19, affecting multiple organ systems and persisting for at least three months post-infection. The global burden of long COVID is staggering, with over 770 million confirmed cases of SARS-CoV-2 infection as of May 2025, and a significant proportion of survivors experiencing persistent symptoms. These symptoms, numbering over 200, span neurological (e.g., brain fog), cardiovascular, gastrointestinal, musculoskeletal, and reproductive systems, leading to an estimated economic loss of USD 3.7 trillion in the United States, equivalent to 17% of its 2019 GDP. The absence of standardized treatments underscores the urgent need for effective therapeutic strategies to mitigate this public health crisis.
Niclosamide, an FDA-approved antiparasitic drug, has emerged as a promising candidate for long COVID management due to its dual antiviral and anti-inflammatory properties. Originally developed to treat intestinal parasitic infections, niclosamide has demonstrated efficacy against SARS-CoV-2 by inhibiting viral replication and mitigating inflammation, key drivers of long COVID pathology. However, its clinical application is limited by poor aqueous solubility (0.23 µg mL⁻¹) and low bioavailability (≈10%), necessitating high oral doses that result in inconsistent plasma levels and potential gastrointestinal side effects. Advances in nanotechnology offer a transformative approach to overcome these pharmacokinetic barriers, enhancing niclosamide’s solubility, bioavailability, and therapeutic efficacy through nanoengineered formulations such as solid lipid nanoparticles (SLNs), liposomes, and inorganic nanohybrids.
1.2 Aim and Scope of the Study
This study aims to critically evaluate the potential of nanoengineered niclosamide as a therapeutic strategy for long COVID management. It reviews the pathophysiology of long COVID, the pharmacological mechanisms of niclosamide, and the role of nanotechnology in addressing its pharmacokinetic limitations. The scope includes an analysis of preclinical and early clinical data, ongoing clinical trials for long COVID treatments, and the regulatory, manufacturing, and economic challenges associated with repurposing niclosamide. By positioning nanoengineered niclosamide within the broader landscape of long COVID management, this review seeks to provide a scientifically grounded perspective for advanced research audiences.
2. Pathophysiology of Long COVID
2.1 Defining Long COVID
Long COVID is characterized by the persistence or emergence of symptoms three months after SARS-CoV-2 infection, lasting for at least two months, as defined by the World Health Organization (WHO). Alternative definitions, such as those by the UK’s National Institute for Health and Care Excellence (NICE), categorize the condition into “ongoing symptomatic COVID-19” (5–12 weeks post-infection) and “post-COVID-19 syndrome” (beyond 12 weeks). Symptoms are highly heterogeneous, affecting multiple systems, including systemic (fatigue, post-exertional malaise), pulmonary (dyspnea), neurological (brain fog, cognitive dysfunction), gastrointestinal, vascular, and musculoskeletal manifestations. Diagnosis remains challenging due to the absence of standardized tests, with over 33% of U.S. patients and 66% of French patients reporting persistent symptoms 60 days post-discharge.
2.2 Underlying Causes
The pathophysiology of long COVID is multifaceted, involving viral persistence, immune dysregulation, and chronic inflammation. Studies indicate that ≈60% of long COVID patients exhibit detectable SARS-CoV-2 fragments in blood up to 12 months post-infection, with viral RNA persisting in stool samples for up to seven months in ≈4% of cases. This persistence suggests the presence of viral reservoirs that continuously produce viral proteins, contributing to ongoing symptoms. Additionally, SARS-CoV-2 induces a dysregulated immune response, characterized by elevated levels of inflammatory markers such as CCL11, which is linked to brain fog. Autopsies and animal studies reveal brain inflammation, complement activation, and vascular damage, underscoring the role of excessive inflammation in neurological symptoms. Autoantibody production further exacerbates systemic inflammation, impacting various organ systems.
3. Niclosamide as a Therapeutic Candidate
3.1 Antiviral Mechanisms
Niclosamide exhibits potent antiviral activity against SARS-CoV-2, with an IC50 of 0.28 µM, as identified through screening of 48 FDA-approved drugs. It inhibits viral replication by neutralizing endosomal pH, a critical step in SARS-CoV-2 entry, and promotes autophagy by inhibiting S-phase kinase-associated protein 2 (SKP2) and stabilizing BECN1. This mechanism is effective across SARS-CoV-2 variants, including alpha (B.1.1.7), beta (B.1.351), and delta (B.1.617.2), with no significant variation in IC50 values. Niclosamide also inhibits replication of other viruses, such as influenza, rhinovirus, chikungunya, and Zika, by attenuating pH-dependent membrane fusion and receptor-mediated endocytosis.
3.2 Anti-Inflammatory and Immunomodulatory Effects
Niclosamide’s anti-inflammatory properties make it a compelling candidate for long COVID. It suppresses inflammasome activation, outperforming 2,560 screened drugs, and inhibits TMEM16 family members (e.g., TMEM16A, TMEM16F) activated by the SARS-CoV-2 spike protein. TMEM16A inhibition reduces NF-κB activation and IL-6 secretion, alleviating airway inflammation, while TMEM16F suppression mitigates spike-induced platelet activation and thrombosis. Niclosamide also decreases IL-8 release, offering potential benefits in chronic inflammatory conditions such as asthma, COPD, and cystic fibrosis, which share inflammatory pathways with long COVID.
3.3 Pharmacological Mechanisms in Long COVID
Niclosamide addresses the core pathological drivers of long COVID through multiple mechanisms: antiviral activity reduces viral load, autophagy regulation clears viral remnants, mitochondrial modulation restores cellular energy balance, and anti-inflammatory effects (via STAT3 inhibition and T cell modulation) mitigate chronic inflammation. Its ability to cross the blood-brain barrier further enables neuroprotective effects, reducing neuroinflammation and addressing neurological symptoms like brain fog. Additionally, its anticoagulant properties via TMEM16F inhibition prevent vascular complications, positioning niclosamide as a versatile therapeutic for long COVID’s multisystemic manifestations.
4. Pharmacokinetic Challenges of Niclosamide
4.1 Solubility and Bioavailability
Niclosamide’s poor aqueous solubility (0.23 µg mL⁻¹) and low bioavailability (≈10%) have limited its systemic efficacy for 60 years. Oral administration results in rapid metabolism in the liver and intestines, primarily via glucuronidation, producing metabolites such as 3-hydroxy niclosamide, amino niclosamide, and niclosamide-2-O-glucuronide. This rapid metabolism reduces systemic exposure, necessitating high doses that lead to inconsistent plasma levels and gastrointestinal side effects.
4.2 Dosage and Administration
Repurposing niclosamide for long COVID requires optimized dosing regimens tailored to chronic conditions. Unlike acute SARS-CoV-2 treatments (e.g., Paxlovid’s 5-day regimen), long COVID may necessitate prolonged administration, as seen in clinical trials extending treatment to 15 days. Ensuring safety over extended periods requires robust Good Laboratory Practice (GLP) toxicity studies to mitigate risks associated with high doses and rapid metabolism.
5. Nanoengineering Strategies to Enhance Niclosamide’s Efficacy
5.1 Overcoming Pharmacokinetic Barriers
Nanotechnology offers innovative solutions to niclosamide’s pharmacokinetic challenges. Nanoengineered formulations enhance solubility, bioavailability, and targeted delivery, improving therapeutic outcomes while reducing systemic toxicity. Key approaches include:
Solid Lipid Nanoparticles (SLNs): Encapsulation in SLNs, composed of egg phosphatidylcholine, cholesterol, and PEGylated lipids, improves gastrointestinal stability and absorption.
Liposomal Formulations: Liposomes protect niclosamide from degradation, enhancing intestinal absorption.
Cyclodextrin Complexes: Inclusion complexes with 4-sulphonato-calix[n]arenes and cyclodextrins increase solubility.
Inorganic Nanoparticles: MgO-based nanohybrids create an alkaline environment to deprotonate niclosamide, enhancing solubility, while hydroxypropyl methylcellulose (HPMC) promotes sustained release.
Polymeric Micelles and Nanocrystals: These improve solubility and dissolution rates, facilitating better absorption.
5.2 Preclinical Evidence
Preclinical studies demonstrate significant improvements with nanoengineered niclosamide. Electrospray technology produced nano-NI colloidal dispersions (105–493 nm), enhancing bioavailability in rats. Amorphous niclosamide formulations with PVP-VA and TPGS achieved a 2.6-fold increase in oral bioavailability in Sprague-Dawley rats. Inorganic nanohybrids like NIC-MgO-HPMC reduced viral load in the lungs of SARS-CoV-2-infected golden Syrian hamsters, suppressed inflammation, and improved bioavailability in human phase 1 and 2 clinical trials compared to traditional niclosamide (Yomesan).
6. Clinical Trials Landscape for Long COVID Treatments
6.1 Current Candidates
Clinical trials for long COVID focus on antiviral and anti-inflammatory strategies. Antiviral agents like nirmatrelvir/ritonavir (Paxlovid), remdesivir (Veklury), and ensitrelvir (Xocova) target viral persistence, while anti-inflammatory drugs such as montelukast (Singulair), sirolimus (Rapamune), and RSLV-132 address chronic inflammation. Other candidates, including AXA1125 and TNX-102 SL, target fatigue and pain, respectively. These trials vary in phase (2–4), enrollment (22–2,000 participants), and endpoints (e.g., quality of life, symptom severity), reflecting the complexity of long COVID.
6.2 Positioning Nanoengineered Niclosamide
Nanoengineered niclosamide complements existing candidates by addressing both viral persistence and inflammation. Its ability to cross the blood-brain barrier offers a unique advantage for neurological symptoms, while its anticoagulant properties mitigate vascular complications. However, clinical evidence for long COVID remains limited, necessitating well-controlled trials to validate its efficacy and safety in this context.
7. Challenges and Opportunities in Repurposing Nanoengineered Niclosamide
7.1 Regulatory and Clinical Considerations
Repurposing niclosamide for long COVID requires navigating regulatory pathways, leveraging its existing FDA approval to expedite authorization. Clinical trials must address long COVID’s heterogeneity by selecting endpoints that capture multisystemic symptom relief and quality-of-life improvements. Adaptive trial designs and investigator-led studies can optimize treatment strategies, particularly for neuropsychiatric symptoms.
7.2 Manufacturing and Economic Barriers
Scaling nanoengineered niclosamide production requires significant infrastructure investment and compliance with quality control standards. Its off-patent status limits commercial incentives, necessitating public funding and international collaborations to support clinical trials and ensure equitable access. Optimized formulations that reduce required doses can lower production costs, enhancing affordability in resource-limited settings.
7.3 Global Impact and Accessibility
Nanoengineered niclosamide’s pre-existing FDA approval and potential for scalable production position it as a cost-effective solution for global health. Its broad-spectrum antiviral and anti-inflammatory properties extend its utility beyond long COVID, offering a multipurpose therapeutic for future viral outbreaks and chronic inflammatory conditions.
8. Future Directions
8.1 Interdisciplinary Research
Successful repurposing of nanoengineered niclosamide requires collaboration across pharmacology, nanotechnology, and clinical medicine. Research should focus on optimizing nanohybridization techniques, exploring combination therapies with other anti-inflammatory agents, and investigating its effects on viral replication and immune pathways. Longitudinal studies are essential to assess long-term efficacy, safety, and health economic impacts.
8.2 Integration into Long COVID Management
Nanoengineered niclosamide should be integrated as a complementary strategy within the evolving landscape of long COVID management. Synergistic approaches with existing candidates can address the multifaceted nature of the disease, while rigorous clinical trials validate its role in improving patient outcomes.
9. Conclusion
Nanoengineered niclosamide represents a promising therapeutic strategy for long COVID, addressing its complex pathophysiology through antiviral, anti-inflammatory, and immunomodulatory mechanisms. Nanotechnology overcomes niclosamide’s longstanding pharmacokinetic challenges, enhancing its solubility, bioavailability, and efficacy, as demonstrated in preclinical and early clinical studies. While challenges in regulatory approval, clinical trial design, and manufacturing scalability remain, the strategic application of nanoengineered niclosamide offers a scalable and accessible solution for global health. Comprehensive clinical trials and interdisciplinary collaboration are critical to realizing its potential, paving the way for innovative treatments that mitigate the ongoing burden of long COVID and prepare for future pandemics.
References
Rejinold, S. N., Choi, G., Jin, G.-W., & Choy, J.-H. (2025). Transforming Niclosamide through Nanotechnology: A Promising Approach for Long COVID Management. Small. https://doi.org/10.1002/smll.202410345
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